isolation-of-sertoli-cells-and-peritubular-cells-from-rat-testes

Isolation of Sertoli Cells and Peritubular Cells from Rat Testes

The testis, and in particular the male gamete, challenges the immune system in a unique way because differentiated sperm first appear at the time of ...

Justus-Liebig-Universität Gießen

Uropathogenic Escherichia coli (UPEC) is the most common etiological cause of urogenital tract infections and represents a considerable cause of immunological male infertility. We examined TLR 1-11 expression profiles in testicular cells and the functional response to infection with UPEC. All testicular cell types expressed mRNAs for at least two TLRs and, in particular, synthesis of TLR4 was induced in testicular macrophages (TM), Sertoli cells (SC), peritubular cells (PTC), and peritoneal macrophages (PM) after UPEC exposure. Even though MyD88-dependent pathways were activated as exemplified by phosphorylation of mitogen-activated protein kinases in TM, SC, PTC, and PM and by the degradation of IkappaBalpha and the nuclear translocation of NF-kappaB in PTC and PM, treatment with UPEC did not result in secretion of the proinflammatory cytokines IL-1alpha, IL-6, and TNF-alpha in any of the investigated cells. Moreover, stimulated production of these cytokines by nonpathogenic commensal E. coli or LPS in PM was completely abolished after coincubation with UPEC. Instead, in SC, PTC, TM, and PM, UPEC exposure resulted in activation of MyD88-independent signaling as documented by nuclear transfer of IFN-related factor-3 and elevated expression of type I IFNs alpha and beta, IFN-gamma-inducible protein 10, MCP-1, and RANTES. We conclude that in this in vitro model UPEC can actively suppress MyD88-dependent signaling at different levels to prevent proinflammatory cytokine secretion by testicular cells. Thus, testicular innate immune defense is shifted to an antiviral-like MyD88-independent response.

Uropathogenic Escherichia coli block MyD88-dependent and activate MyD88-independent signaling pathways in rat testicular cells.

Infection and inflammation are relevant entities of male factor infertility. Bacterial infections are mostly the consequence of an ascending infection of the genito-urinary tract which can ultimately lead to epididymo-orchitis. Bacterial toxins and the innate immune responses directed against them may have a significant impact on male reproductive function. Toll-like receptors (TLRs) constitute the major family of pattern recognition receptors that play a pivotal role in innate immunity. In the testis, TLRs are not only found in immune cells such as macrophages and dendritic cells, but also in testicular somatic cells and to a lesser extent in germ cells. In this review we describe relevant bacterial pathogens found in testicular and male reproductive tract infection, new data on the localisation and potential functions of TLRs, recognition and response to bacteria with a special emphasis on uropathogenic Escherichia coli. Mechanisms by which uropathogenic E. coli subvert innate immune responses in the testis are discussed using information derived from animal model studies.

Testicular innate immune defense against bacteria.

The male reproductive tract harbours effective immune mechanisms to protect the host from invading microorganisms. As the frontline of defence, the innate immune system has evolved receptors that recognise molecular patterns of pathogens to sense infections. These Toll-like receptors discriminate between different pathogen-associated molecules and activate signalling cascades that lead to immune responses, but can also result in tissue destruction leading to fertility disturbances. The testis is unique as it produces a large number of immunogenic cells expressing neo-antigens with no apparent adverse consequences for the majority of men. On the other hand the male gonad appears to be particularly susceptible to tissue damage resulting from infection or inflammatory reactions, a challenge that provides an important task both to clinicians and basic scientists. This review is intended to provide an overview of pathogens relevant in male reproductive tract infection, with a special emphasis on the testis. It also highlights the recent work broadening our understanding of the mechanisms underpinning germ cell loss in the presence of bacteria.

Testicular infection: microorganisms, clinical implications and host-pathogen interaction.

The testis is an immunological privileged tissue as evidenced by its ability to support grafts with minimal rejection. Immune privilege is essential for the tolerance of neo-antigens from developing germ cells that appear after the constitution of self-tolerance, but imposes the paradoxical task of also providing efficient protection against pathogens and tumor cells. It is becoming increasingly clear that immune privilege cannot be attributed to a single factor such as the sequestration of neo-antigens from the immune system behind the blood-testis barrier, but is based on a complex multifaceted interplay between cells and factors that are essential for the reproductive function of the testis and the testicular immune system. This review summarizes the evidence that has accumulated regarding the role of Sertoli cells, androgens, and selected population of leukocytes in the maintenance of immune privilege and its perturbation in testicular inflammatory sub- and infertility.

Immunoprivileged sites: the testis.

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Despite the immune-privileged status of the male genital tract, infection and inflammation of the male genital tract are important etiological factors in male infertility. A common observation in clinical and experimental orchitis as well as in systemic infection and inflammation are decreased levels of testosterone. Emerging data point to an immunosuppressive role of testosterone. In our study, we substituted testosterone levels in experimental autoimmune orchitis (EAO) in rat by s.c. testosterone implants. EAO development was reduced to 17% when animals were treated with low-dose testosterone implants (3 cm long, EAO+T3) and to 33% when rats were supplied with high-dose testosterone implants (24 cm, EAO+T24) compared with 80% of animals developing disease in the EAO control group. In the testis, testosterone replacement in EAO animals prevented the accumulation of macrophages and significantly reduced the number of CD4(+) T cells with a strong concomitant increase in the number of regulatory T cells (CD4(+)CD25(+)Foxp3(+)) compared with EAO control. In vitro testosterone treatment of naive T cells led to an expansion of the regulatory T cell subset with suppressive activity and ameliorated MCP-1-stimulated chemotaxis of T lymphocytes in a Transwell assay. Moreover, expression of proinflammatory mediators such as MCP-1, TNF-Î±, and IL-6 in the testis and secretion of Th1 cytokines such as IFN-Î³ and IL-2 by mononuclear cells isolated from testicular draining lymph nodes were decreased in the EAO+T3 and EAO+T24 groups. Thus, our study shows an immunomodulatory and protective effect of testosterone substitution in the pathogenesis of EAO and suggests androgens as a new factor in the differentiation of regulatory T cells.

Testosterone replacement effectively inhibits the development of experimental autoimmune orchitis in rats: evidence for a direct role of testosterone on regulatory T cell expansion.

Malgr&#xE9; le statut immunitaire privil&#xE9;gi&#xE9; de l&#x26;#39;appareil m&#xE2;le, l&#x26;#39;infection g&#xE9;nitale et de l&#x26;#39;inflammation du tractus g&#xE9;nital masculin sont d&#x26;#39;importants facteurs &#xE9;tiologiques dans l&#x26;#39;infertilit&#xE9; masculine. Une observation commune dans l&#x26;#39;orchite clinique et exp&#xE9;rimentale ainsi que dans l&#x26;#39;infection syst&#xE9;mique et l&#x26;#39;inflammation sont une diminution des niveaux de testost&#xE9;rone. De nouvelles donn&#xE9;es indiquent un r&#xF4;le immunosuppresseur de la testost&#xE9;rone. Dans notre &#xE9;tude, nous avons substitu&#xE9; le taux de testost&#xE9;rone dans l&#x26;#39;orchite auto-immune exp&#xE9;rimentale (EAO) chez le rat par des implants de testost&#xE9;rone sc. EAO d&#xE9;veloppement a &#xE9;t&#xE9; r&#xE9;duite &#xE0; 17% lorsque les animaux ont &#xE9;t&#xE9; trait&#xE9;s avec des implants de testost&#xE9;rone &#xE0; faible dose (3 cm de long, EAO + t3) et &#xE0; 33% lorsque les rats ont &#xE9;t&#xE9; fournies avec les implants de testost&#xE9;rone &#xE0; dose &#xE9;lev&#xE9;e (24 cm, EAO + T24) par rapport &#xE0; 80% des animaux d&#xE9;velopper la maladie dans le groupe t&#xE9;moin EAO. Dans le testicule, remplacement de la testost&#xE9;rone chez les animaux EAO a emp&#xEA;ch&#xE9; l&#x26;#39;accumulation de macrophages et de r&#xE9;duire consid&#xE9;rablement le nombre de CD4 (+) des cellules T avec une augmentation concomitante forte augmentation du nombre de cellules T r&#xE9;gulatrices (CD4 (+) CD25 (+) Foxp3 (+ )) par rapport &#xE0; l&#x26;#39;EAO de contr&#xF4;le. En traitement &#xE0; la testost&#xE9;rone in vitro des cellules T na&#xEF;ves conduit &#xE0; une expansion du sous-ensemble de cellules T r&#xE9;gulatrices de l&#x26;#39;activit&#xE9; suppressive et am&#xE9;lior&#xE9; MCP-1-stimulait la chimiotaxie des lymphocytes T dans un dosage Transwell. En outre, l&#x26;#39;expression de m&#xE9;diateurs pro-inflammatoires tels que MCP-1, TNF-&#x3B1;, IL-6 et dans les testicules et la s&#xE9;cr&#xE9;tion de cytokines Th1 comme l&#x26;#39;IFN-&#x3B3; et d&#x26;#39;IL-2 par les cellules mononucl&#xE9;&#xE9;es isol&#xE9;es &#xE0; partir des n&#x153;uds lymphatiques drainant testiculaires ont diminu&#xE9; dans la EAO + T3 et T24 + groupes EAO. Ainsi, notre &#xE9;tude montre un effet protecteur immunomodulateur et de substitution de testost&#xE9;rone dans la pathogen&#xE8;se de l&#x26;#39;EAO et sugg&#xE8;re androg&#xE8;nes comme un nouveau facteur dans la diff&#xE9;renciation des cellules T r&#xE9;gulatrices.

Remplacement de la testost&#xE9;rone inhibe efficacement le d&#xE9;veloppement de l&#x26;#39;orchite auto-immune exp&#xE9;rimentale chez le rat: Les preuves d&#x26;#39;un r&#xF4;le direct de la testost&#xE9;rone sur l&#x26;#39;expansion des cellules T r&#xE9;gulatrices

Trotz der immunen privilegierten Status der m&auml;nnlichen Genitaltrakt sind Infektion und Entz&uuml;ndung der m&auml;nnlichen Genitaltrakt wichtige &auml;tiologische Faktoren f&uuml;r m&auml;nnliche Unfruchtbarkeit. Eine gemeinsame Beobachtung im klinischen und experimentellen Orchitis sowie systemische Infektion und Entz&uuml;ndung verringerte Niveaus des Testosterons sind. Neue Daten zeigen eine immunsuppressive Rolle von Testosteron. In unserer Studie ersetzt wir Testosteronspiegel in experimentelle autoimmune Orchitis (EAO) Ratte von s.c. Testosteron Implantate. EAO-Entwicklung wurde auf 17 % reduziert, wenn Tiere behandelt wurden, mit niedrig dosiertes Testosteron Implantate (3 cm lang, EAO + T3) und 33 % bei Ratten mit hoch dosierten Testosteron Implantate (24 cm, EAO + T24) gegen&uuml;ber 80 % der Tiere, die Entwicklung der Krankheit in der EAO-Kontrollgruppe geliefert wurden. In den Hoden Testosteron-Ersatz in EAO Tiere verhindert die Ansammlung von Makrophagen und deutlich reduziert die Anzahl der CD4(+) T-Zellen mit einer starken damit einhergehende Zunahme von regulatorischen T-Zellen (CD4(+)CD25(+)Foxp3(+)) gegen&uuml;ber EAO-Steuerelement. In-vitro-Testosteron-Behandlung von naiven T-Zellen f&uuml;hrte zu einer Ausweitung der regulatorische T-Zelle Teilmenge mit unterdr&uuml;ckende Aktivit&auml;t und MCP-1-stimuliert Chemotaxis von T-Lymphozyten in einem Transwell-Assay einged&auml;mmt. Dar&uuml;ber hinaus wurden Ausdruck der Proinflammatory Vermittler wie MCP-1, TNF-&alpha; und IL-6 in den Hoden und Sekretion von Th1-Zytokine wie IFN-&gamma; und Il von mononukle&auml;ren Zellen isoliert von testikul&auml;ren Drainierende Lymphknoten gesenkt, in den Gruppen EAO + T3 und EAO + T24. Damit unsere Studie zeigt eine immunmodulatorische und sch&uuml;tzende Wirkung von Testosteron-Substitution in der Pathogenese von EAO und schl&auml;gt Androgene als neuer Faktor f&uuml;r die Differenzierung der regulatorischen T-Zellen.

Testosteron-Ersatz wirksam hemmt die Entwicklung der experimentelle autoimmune Orchitis bei Ratten: Beweise f&uuml;r eine direkte Rolle von Testosteron auf regulatorische T-Zell-Expansion.

Nonostante lo stato immunitario privilegiato del tratto genitale maschile, infezioni e infiammazioni dell&#39;apparato genitale maschile sono importanti fattori eziologici nell&#39;infertilit&agrave; maschile. Una comune osservazione in clinica e sperimentale orchite cos&igrave; come nell&#39;infiammazione e infezione sistemica sono la diminuzione dei livelli di testosterone. Dati emergenti indicano un ruolo immunosoppressivo di testosterone. Nel nostro studio, abbiamo sostituito con livelli di testosterone in orchite autoimmune sperimentale (OEA) nel ratto da protesi testosterone s.c.. Sviluppo OEA &egrave; stata ridotta al 17% quando gli animali sono stati trattati con impianti di bassa dose di testosterone (3 cm di lunghezza, EAO + T3) e al 33% quando i ratti sono stati forniti con impianti di testosterone ad alte dosi (24 cm, EAO + T24) confrontati con l&#39;80% degli animali, lo sviluppo di malattia nel gruppo di controllo EAO. Nel testicolo, testosterone sostituzione negli animali OEA ha impedito l&#39;accumulo di macrofagi e notevolmente ridotto il numero di cellule T CD4(+) con un forte concomitante aumento del numero di cellule T regolatorie (CD4(+)CD25(+)Foxp3(+)) confrontato con controllo EAO. Trattamento di testosterone in vitro di cellule T naive ha condotto ad un&#39;espansione del sottoinsieme normativo delle cellule T con attivit&agrave; soppressiva e migliorata di MCP-1-stimolato chemiotassi dei linfociti T in un dosaggio di Transwell. Inoltre, espressione di mediatori proinfiammatori come MCP-1, TNF-&alpha; e IL-6 nel testicolo e la secrezione di citochine Th1 IFN-&gamma; e IL-2 da cellule mononucleate isolato da linfonodi drenanti testicolare sono diminuiti nei gruppi EAO + T3 ed EAO + T24. Cos&igrave;, il nostro studio mostra un effetto protettivo della sostituzione del testosterone e immunomodulatori nella patogenesi dell&#39;EAO e suggerisce gli androgeni come un nuovo fattore nella differenziazione delle cellule T regolatorie.

Sostituzione di testosterone inibisce efficacemente lo sviluppo di orchite autoimmune sperimentale nei ratti: prova per un ruolo diretto di testosterone su espansione di cellule T regolatori.

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+ T24&#xFF09;&#x306B;&#x4ED8;&#x5C5E;&#x3057;&#x3066;&#x3044;&#x305F;&#x3068;&#x304D;&#x306B;&#x52D5;&#x7269;&#x306F;&#x3001;&#x4F4E;&#x7528;&#x91CF;&#x306E;&#x30C6;&#x30B9;&#x30C8;&#x30B9;&#x30C6;&#x30ED;&#x30F3;&#x30A4;&#x30F3;&#x30D7;&#x30E9;&#x30F3;&#x30C8;&#xFF08;&#x9577;&#x3055;3&#x30BB;&#x30F3;&#x30C1;&#x3001;EAO + T3&#xFF09;&#x3067;&#x3001;33&#xFF05;&#x306B;&#x6CBB;&#x7642;&#x3092;&#x53D7;&#x3051;&#x305F;&#x3068;&#x304D;&#x306B;EAO&#x958B;&#x767A;&#x306F;17&#xFF05;&#x306B;&#x6E1B;&#x5C11;&#x3057;&#x305F;EAO&#x306E;&#x5BFE;&#x7167;&#x7FA4;&#x3067;&#x306F;&#x75BE;&#x60A3;&#x3092;&#x767A;&#x75C7;&#x3059;&#x308B;&#x52D5;&#x7269;&#x306E;80&#xFF05;&#x3002;&#x7CBE;&#x5DE3;&#x3067;&#x306F;&#x3001;EAO&#x52D5;&#x7269;&#x306E;&#x30C6;&#x30B9;&#x30C8;&#x30B9;&#x30C6;&#x30ED;&#x30F3;&#x88DC;&#x5145;&#x306F;&#x3001;&#x30DE;&#x30AF;&#x30ED;&#x30D5;&#x30A1;&#x30FC;&#x30B8;&#x306E;&#x84C4;&#x7A4D;&#x3092;&#x9632;&#x6B62;&#x3057;&#x3001;&#x5927;&#x5E45;&#x306B;CD4&#x306E;&#x6570;&#xFF08;+&#xFF09;&#x8ABF;&#x7BC0;&#x6027;T&#x7D30;&#x80DE;&#xFF08;CD4&#xFF08;+&#xFF09;CD25&#xFF08;+&#xFF09;Foxp3&#x306F;&#xFF08;+&#x306E;&#x6570;&#x306E;&#x5F37;&#x529B;&#x306A;&#x4ED8;&#x968F;&#x5897;&#x52A0;&#x3068;&#x3068;&#x3082;&#x306B;T&#x7D30;&#x80DE;&#x3092;&#x6E1B;&#x5C11;&#x3055;&#x305B;&#xFF09;&#xFF09;EAO&#x30B3;&#x30F3;&#x30C8;&#x30ED;&#x30FC;&#x30EB;&#x3068;&#x6BD4;&#x8F03;&#x3057;&#x305F;&#x3002;&#x30CA;&#x30A4;&#x30FC;&#x30D6;T&#x7D30;&#x80DE;&#x306E;in vitro&#x3067;&#x306E;&#x30C6;&#x30B9;&#x30C8;&#x30B9;&#x30C6;&#x30ED;&#x30F3;&#x6CBB;&#x7642;&#x306B;&#x6291;&#x5236;&#x6D3B;&#x6027;&#x304A;&#x3088;&#x3073;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30A6;&#x30A7;&#x30EB;&#x30A2;&#x30C3;&#x30BB;&#x30A4;&#x306B;&#x304A;&#x3051;&#x308B;T&#x30EA;&#x30F3;&#x30D1;&#x7403;&#x306E;&#x6539;&#x5584;MCP-1&#x523A;&#x6FC0;&#x306B;&#x3088;&#x308B;&#x8D70;&#x5316;&#x6027;&#x3068;&#x5236;&#x5FA1;&#x6027;T&#x7D30;&#x80DE;&#x30B5;&#x30D6;&#x30BB;&#x30C3;&#x30C8;&#x306E;&#x62E1;&#x5927;&#x306B;&#x200B;&#x200B;&#x3064;&#x306A;&#x304C;&#x3063;&#x305F;&#x3002;&#x307E;&#x305F;&#x3001;&#x3053;&#x306E;&#x3088;&#x3046;&#x306A;MCP-1&#x3001;TNF-&#x3B1;&#x3001;&#x304A;&#x3088;&#x3073;&#x200B;&#x200B;&#x7CBE;&#x5DE3;&#x6240;&#x5C5E;&#x30EA;&#x30F3;&#x30D1;&#x7BC0;&#x304B;&#x3089;&#x5206;&#x96E2;&#x3055;&#x308C;&#x308B;&#x5358;&#x6838;&#x7D30;&#x80DE;&#x306B;&#x3088;&#x308B;&#x3053;&#x306E;&#x3088;&#x3046;&#x306A;IFN-&#x3B3;&#x304A;&#x3088;&#x3073;IL-2&#x306A;&#x3069;&#x306E;Th1&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;&#x306E;&#x7CBE;&#x5DE3;&#x304A;&#x3088;&#x3073;&#x5206;&#x6CCC;&#x306E;IL-6&#x306A;&#x3069;&#x306E;&#x708E;&#x75C7;&#x6027;&#x30E1;&#x30C7;&#x30A3;&#x30A8;&#x30FC;&#x30BF;&#x30FC;&#x306E;&#x767A;&#x73FE;&#x304C;&#x4F4E;&#x4E0B;&#x3057;&#x3066;&#x3044;&#x305F;EAO + T3&#x304A;&#x3088;&#x3073;EAO + T24&#x30B0;&#x30EB;&#x30FC;&#x30D7;&#x3002;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;&#x6211;&#x3005;&#x306E;&#x7814;&#x7A76;&#x3067;&#x306F;&#x3001;EAO&#x306E;&#x75C5;&#x56E0;&#x306B;&#x514D;&#x75AB;&#x3068;&#x30C6;&#x30B9;&#x30C8;&#x30B9;&#x30C6;&#x30ED;&#x30F3;&#x7F6E;&#x63DB;&#x306E;&#x4FDD;&#x8B77;&#x52B9;&#x679C;&#x3092;&#x793A;&#x3057;&#x3001;&#x8ABF;&#x7BC0;&#x6027;T&#x7D30;&#x80DE;&#x306E;&#x5206;&#x5316;&#x306E;&#x65B0;&#x305F;&#x306A;&#x56E0;&#x5B50;&#x3068;&#x3057;&#x3066;&#x30A2;&#x30F3;&#x30C9;&#x30ED;&#x30B2;&#x30F3;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;

&#x30C6;&#x30B9;&#x30C8;&#x30B9;&#x30C6;&#x30ED;&#x30F3;&#x88DC;&#x5145;&#x304C;&#x52B9;&#x679C;&#x7684;&#x306B;&#x30E9;&#x30C3;&#x30C8;&#x306B;&#x304A;&#x3051;&#x308B;&#x5B9F;&#x9A13;&#x7684;&#x81EA;&#x5DF1;&#x514D;&#x75AB;&#x6027;&#x7CBE;&#x5DE3;&#x708E;&#x306E;&#x958B;&#x767A;&#x3092;&#x963B;&#x5BB3;&#x3059;&#x308B;&#xFF1A;&#x5236;&#x5FA1;&#x6027;T&#x7D30;&#x80DE;&#x81A8;&#x5F35;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x30C6;&#x30B9;&#x30C8;&#x30B9;&#x30C6;&#x30ED;&#x30F3;&#x306E;&#x76F4;&#x63A5;&#x7684;&#x306A;&#x5F79;&#x5272;&#x306E;&#x8A3C;&#x62E0;

&#xB0A8;&#xC131; &#xC131; &#xAE30; &#xC694;&#xB85C; &#xBA74;&#xC5ED; &#xAD8C;&#xD55C; &#xC0C1;&#xD0DC;&#xC5D0;&#xB3C4; &#xBD88;&#xAD6C; &#xD558; &#xACE0; &#xB0A8;&#xC131; &#xC131; &#xAE30; &#xC694;&#xB85C;&#xC758; &#xC5FC;&#xC99D; &#xBC0F; &#xAC10;&#xC5FC; &#xC694;&#xC778;&#xC774; &#xC911;&#xC694; &#xD55C; etiological &#xB0A8;&#xC131; &#xBD88; &#xC784;&#xC5D0;. &#xC784;&#xC0C1; &#xBC0F; &#xC2E4;&#xD5D8; orchitis &#xBFD0;&#xB9CC; &#xC544;&#xB2C8;&#xB77C; &#xC870;&#xC9C1;&#xC758; &#xAC10;&#xC5FC; &#xBC0F; &#xC5FC;&#xC99D;&#xC5D0;&#xB294; &#xB0A8;&#xC131; &#xD638;&#xB974;&#xBAAC;&#xC758; &#xAC10;&#xC18C; &#xC218;&#xC900;&#xC5D0;&#xC11C;&#xC5D0;&#xC11C; &#xC77C;&#xBC18;&#xC801;&#xC778; &#xAD00;&#xCC30;. &#xC2E0;&#xD765; &#xB370;&#xC774;&#xD130; &#xC2A4;&#xD1A0;&#xC758; &#xBA74;&#xC5ED; &#xC5ED;&#xD560;&#xC744; &#xAC00;&#xB9AC;&#xD0B5;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xC758; &#xC5F0;&#xAD6C;&#xC5D0;&#xC11C; &#xC6B0;&#xB9AC; &#xC0AC;&#xC6B0;&#xC2A4; &#xCE90;&#xB864;&#xB77C;&#xC774;&#xB098; &#xC2A4;&#xD1A0; &#xC784; &#xD50C; &#xB780; &#xD2B8;&#xC5D0; &#xC758;&#xD574; &#xC950;&#xC5D0; &#xC2E4;&#xD5D8; &#xC790;&#xAC00; &#xBA74;&#xC5ED; orchitis (EAO)&#xC5D0;&#xC11C; &#xD14C; &#xC2A4;&#xD1A0; &#xC2A4; &#xD14C; &#xB808;&#xBCA8; &#xB300;&#xCCB4;. &#xB3D9;&#xBB3C; &#xC950; &#xB192;&#xC740; &#xBCF5;&#xC6A9;&#xB7C9; &#xD14C; &#xC2A4;&#xD1A0; &#xC2A4; &#xD14C; &#xC784; &#xD50C; &#xB780; &#xD2B8; (24 cm, EAO + T24) &#xB3D9;&#xBB3C; EAO &#xCEE8;&#xD2B8;&#xB864; &#xADF8;&#xB8F9;&#xC5D0; &#xC788;&#xB294; &#xC9C8;&#xBCD1;&#xC744; &#xAC1C;&#xBC1C;&#xC758; 80%&#xC5D0; &#xBE44;&#xD574; &#xD568;&#xAED8; &#xC81C;&#xACF5; &#xB41C; &#xACBD;&#xC6B0; &#xB0AE;&#xC740; &#xBCF5;&#xC6A9;&#xB7C9; &#xD14C; &#xC2A4;&#xD1A0; &#xC2A4; &#xD14C; &#xC784; &#xD50C; &#xB780; &#xD2B8; (3cm &#xAE38;&#xC774;, EAO + T3)&#xC640; 33%&#xB97C; &#xCE58;&#xB8CC; &#xD588;&#xB2E4; EAO &#xAC1C;&#xBC1C;&#xC774; 17% &#xAC10;&#xC18C; &#xD588;&#xB2E4;. &#xACE0;&#xD658;, EAO &#xB3D9;&#xBB3C;&#xC5D0; &#xC2A4;&#xD1A0; &#xAD50;&#xCCB4; &#xB300; &#xC2DD; &#xC138;&#xD3EC;&#xC758; &#xCD95;&#xC801;&#xC744; &#xBC29;&#xD574; &#xD558; &#xACE0; &#xD06C;&#xAC8C; &#xADDC;&#xC81C; T &#xC138;&#xD3EC; (EAO &#xCEE8;&#xD2B8;&#xB864;&#xACFC; &#xBE44;&#xAD50; CD4(+)CD25(+)Foxp3(+)) &#xC218; &#xAC15;&#xD55C; &#xC218; &#xBC18;&#xD558;&#xB294; &#xC99D;&#xAC00; CD4(+) T &#xC138;&#xD3EC;&#xC758; &#xC218;&#xB97C; &#xAC10;&#xC18C;. &#xC21C;&#xC9C4;&#xD55C; T &#xC138;&#xD3EC;&#xC758; &#xC0DD;&#xCCB4; &#xC678;&#xC5D0;&#xC11C; &#xC2A4;&#xD1A0; &#xCE58;&#xB8CC; &#xC9C4;&#xC555; &#xD65C;&#xB3D9; &#xADDC;&#xC81C; T &#xC138;&#xD3EC; &#xD558;&#xC704; &#xC9D1;&#xD569;&#xC758; &#xD655;&#xC7A5;&#xC744; &#xC8FC;&#xB3C4;&#xD558; &#xACE0; ameliorated Transwell &#xBD84;&#xC11D; &#xACB0;&#xACFC;&#xC5D0;&#xC11C; T &#xB9BC;&#xD504; &#xD1A8;&#xC758; chemotaxis MCP 1 &#xC790;&#xADF9;. &#xB610;&#xD55C;, MCP 1, TNF-&alpha;&#xB294; &#xACE0;&#xD658;&#xC5D0;&#xC11C; &#xC77C;&#xB9AC;&#xB178;&#xC774;-6 &#xB4F1; proinflammatory &#xC911;&#xC7AC;&#xC790;&#xC758; &#xD45C;&#xD604;&#xACFC; IFN-&gamma;&#xC640; &#xACE0;&#xD658; &#xBC30;&#xCD9C; &#xB9BC;&#xD504;&#xC808;&#xC5D0;&#xC11C; &#xACE0;&#xB9BD; &#xB41C; &#xB2E8; &#xC138;&#xD3EC;&#xC5D0; &#xC758;&#xD574; &#xC77C;&#xB9AC;&#xB178;&#xC774;-2&#xC640; &#xAC19;&#xC740; Th1 cytokines&#xC758; &#xBD84; &#xBE44;&#xB294; EAO + t 3&#xC640; EAO + T24 &#xADF8;&#xB8F9;&#xC5D0;&#xC11C; &#xAC10;&#xC18C; &#xD588;&#xB2E4;. &#xB530;&#xB77C;&#xC11C;, &#xC6B0;&#xB9AC;&#xC758; &#xC5F0;&#xAD6C; EAO&#xC758; pathogenesis&#xC758; immunomodulatory&#xC640; &#xB0A8;&#xC131; &#xD638;&#xB974;&#xBAAC; &#xB300;&#xCCB4;&#xC758; &#xBCF4;&#xD638; &#xD6A8;&#xACFC; &#xBCF4;&#xC5EC;&#xC900;&#xB2E4; &#xACE0; &#xADDC;&#xC81C; T &#xC138;&#xD3EC;&#xC758; &#xBD84;&#xD654;&#xC5D0; &#xC0C8;&#xB85C;&#xC6B4; &#xC694;&#xC18C;&#xB85C; androgens&#xC744; &#xC81C;&#xC548; &#xD569;&#xB2C8;&#xB2E4;.

&#xD14C; &#xC2A4;&#xD1A0; &#xD14C; &#xB860; &#xB300;&#xCCB4; &#xD6A8;&#xACFC;&#xC801;&#xC73C;&#xB85C; &#xC950;&#xC5D0; &#xC2E4;&#xD5D8; &#xC790;&#xAC00; &#xBA74;&#xC5ED; orchitis&#xC758; &#xAC1C;&#xBC1C; &#xC5B5;&#xC81C;: &#xADDC;&#xC81C; T &#xC138;&#xD3EC; &#xD655;&#xC7A5;&#xC5D0; &#xC2A4;&#xD1A0;&#xC758; &#xC9C1;&#xC811;&#xC801;&#xC778; &#xC5ED;&#xD560;&#xC5D0; &#xB300; &#xD55C; &#xC99D;&#xAC70;.

A pesar de la situaci&#xF3;n privilegiada de la inmunidad del tracto genital masculino infecci&#xF3;n y la inflamaci&#xF3;n del tracto genital masculino son importantes factores etiol&#xF3;gicos en la infertilidad masculina. Una observaci&#xF3;n com&#xFA;n en orquitis cl&#xED;nica y experimental, as&#xED; como en la infecci&#xF3;n sist&#xE9;mica y la inflamaci&#xF3;n se reducen los niveles de testosterona. Los datos emergentes apuntan a un papel inmunosupresor de la testosterona. En nuestro estudio, hemos sustituido los niveles de testosterona en la orquitis autoinmune experimental (OAE), en la rata por los implantes de testosterona sc. EAO el desarrollo se redujo a 17% cuando los animales fueron tratados con implantes de testosterona en dosis bajas (3 cm de largo, la EAO + T3) y al 33% cuando las ratas se les suministr&#xF3; los implantes de testosterona de dosis alta (24 cm, la EAO + T24) en comparaci&#xF3;n con 80% de los animales en desarrollo de la enfermedad en el grupo de control EAO. En el test&#xED;culo, el reemplazo de testosterona en animales EAO impedido la acumulaci&#xF3;n de macr&#xF3;fagos y redujo significativamente el n&#xFA;mero de CD4 (+) las c&#xE9;lulas T con un incremento concomitante fuerte en el n&#xFA;mero de c&#xE9;lulas T reguladoras (CD4 (+) CD25 (+) Foxp3 (+ )) en comparaci&#xF3;n con la EAO de control. En el tratamiento de testosterona in vitro de c&#xE9;lulas T ingenuas llevaron a una expansi&#xF3;n del subconjunto de c&#xE9;lulas T reguladoras con actividad supresora y mejorado de MCP-1-estimulado la quimiotaxis de linfocitos T en un ensayo Transwell. Por otra parte, la expresi&#xF3;n de mediadores proinflamatorios, como MCP-1, TNF-&#x3B1; e IL-6 en el test&#xED;culo y la secreci&#xF3;n de citoquinas Th1 como el IFN-&#x3B3; e IL-2 por c&#xE9;lulas mononucleares aisladas de los ganglios linf&#xE1;ticos que drenan los test&#xED;culos se redujeron en el EAO + T3 y T24 + grupos EAO. Por lo tanto, nuestro estudio muestra un inmunomodulador y efecto protector de la sustituci&#xF3;n de la testosterona en la patog&#xE9;nesis de la EAO y sugiere los andr&#xF3;genos como un nuevo factor en la diferenciaci&#xF3;n de las c&#xE9;lulas T reguladoras.

El reemplazo de testosterona inhibe eficazmente el desarrollo de la orquitis autoinmune experimental en ratas: evidencia de un papel directo de la testosterona sobre la expansi&#xF3;n de c&#xE9;lulas T reguladoras

&#x4E0D;&#x5B55;&#x592B;&#x5987;&#x4E03;&#x5206;&#x4E4B;&#x4E00;&#x548C;&#x5927;&#x80A0;&#x57C3;&#x5E0C;&#x83CC;&#x6309;&#x5347;&#x5E8F;&#x7684;&#x7537;&#x6027;&#x6CCC;&#x5C3F;&#x751F;&#x6B96;&#x9053;&#x7EC6;&#x83CC;&#x611F;&#x67D3;&#x5927;&#x80A0;&#x6746;&#x83CC;&#x662F;&#x7537;&#x6027;&#x4E0D;&#x5B55;&#x75C7;&#x7684;&#x4E00;&#x4E2A;&#x91CD;&#x8981;&#x539F;&#x56E0;&#x3002;&#x56E0;&#x6B64;&#x4E86;&#x89E3;&#x54EA;&#x4E9B;&#x514D;&#x75AB;&#x6D3B;&#x6027;&#x7EC6;&#x80DE;&#x7684;&#x673A;&#x5236;&#xFF0C;&#x5982;&#x777E;&#x4E38;&#x5DE8;&#x566C;&#x7EC6;&#x80DE; (TM) &#x56DE;&#x5E94;&#x611F;&#x67D3;&#x548C;&#x7EC6;&#x83CC;&#x75C5;&#x539F;&#x4F53;&#x64CD;&#x4F5C;&#x9632;&#x5FA1;&#x9014;&#x5F84;&#x5982;&#x4F55;&#x662F;&#x91CD;&#x8981;&#x7684;&#x3002;&#x5168;&#x57FA;&#x56E0;&#x7EC4;&#x8868;&#x8FBE;&#x8C31;&#x7684; TM &#x548C;&#x8179;&#x8154;&#x5DE8;&#x566C;&#x7EC6;&#x80DE; &#xFF08;PM&#xFF09; &#x611F;&#x67D3;&#x81F4;&#x80BE;&#x76C2;&#x80BE;&#x708E;&#x5927;&#x80A0;&#x6746;&#x83CC; (UPEC) &#x53D1;&#x73B0;&#x8C03;&#x8282;&#x57FA;&#x56E0;&#x7684;&#x4E3B;&#x8981;&#x5DEE;&#x5F02;&#x3002;&#x7136;&#x800C;&#xFF0C;&#x5927;&#x91CF;&#x7684;&#x9499;&#x4FE1;&#x53F7;&#x901A;&#x8DEF;&#x4E2D;&#x53D7;&#x7275;&#x8FDE;&#x7684;&#x57FA;&#x56E0;&#x662F;&#x8868;&#x793A;&#x9499;&#x4F9D;&#x8D56;&#x6838;&#x56E0;&#x5B50;&#x7684;&#x6D3B;&#x6027; T &#x7EC6;&#x80DE; (NFAT) &#x4FE1;&#x53F7;&#x7684;&#x4F5C;&#x7528;&#x7684;&#x4E00;&#x4E2A;&#x5171;&#x540C;&#x7279;&#x70B9;&#x3002;UPEC &#x4F9D;&#x8D56; NFAT &#x6FC0;&#x6D3B;&#x4F53;&#x5185;&#x7684; UPEC &#x4F20;&#x67D3;&#x6027;&#x5927;&#x9F20;&#x777E;&#x4E38;&#x708E;&#x6A21;&#x578B;&#x4E2D;&#x8BC1;&#x5B9E;&#x5728;&#x8FD9;&#x4E24;&#x79CD;&#x7EC6;&#x80DE;&#x7684; TM &#x548C; TM&#x3002;&#x9AD8;&#x67B6;&#x7684; NFATC2 &#x8C03;&#x8282;&#x6297;&#x708E;&#x7EC6;&#x80DE;&#x56E0;&#x5B50;&#x7684;&#x8868;&#x8FBE;&#x88AB;&#x53D1;&#x73B0;&#x5728; TM (IL-4&#xFF0C;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-13&#xFF09; &#x548C;&#x4E0B;&#x5348; (&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-3&#x3001; IL 4&#x3001; IL-13&#xFF09;&#x3002;NFATC2 &#x662F;&#x7531;&#x9499;&#x3001; &#x5212;&#x5B9A;&#x7684;&#x5B54;&#x9699;&#x5F62;&#x6210;&#x6BD2;&#x7D20; &alpha;-&#x6EB6;&#x8840;&#x7D20;&#x7684;&#x7EC6;&#x83CC;&#x7A81;&#x53D8;&#x5206;&#x6790;&#x6D3B;&#x52A8;&#x8FC5;&#x901F;&#x6D8C;&#x5165;&#x6FC0;&#x6D3B;&#x3002;&Alpha;-&#x6EB6;&#x8840;&#x7D20;&#x6291;&#x5236;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-6 &#x548C;&#x80BF;&#x7624;&#x574F;&#x6B7B;&#x56E0;&#x5B50;-&alpha; &#x7EC6;&#x80DE;&#x56E0;&#x5B50;&#x91CA;&#x653E;&#x4ECE;&#x4E0B;&#x5348;&#x548C; TM &#x548C;&#x4E0B;&#x5348;&#x4E0B;&#x5348; (IL 1&alpha;&#xFF0C;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-1&beta; IL-6 &#x7F16;&#x7801;&#xFF09; &#x5173;&#x952E; pro &#x708E;&#x6027;&#x7EC6;&#x80DE;&#x56E0;&#x5B50;&#x7684;&#x76F8;&#x4E92;&#x8868;&#x8FBE;&#x5BFC;&#x81F4;&#x9020;&#x6210;&#x5DEE;&#x5F02; MAP &#x6FC0;&#x9176;&#x548C; AP 1 &#x4FE1;&#x53F7;&#x901A;&#x8DEF;&#x7684;&#x6FC0;&#x6D3B;&#x548C; TM (IL-6 &#x589E;&#x9AD8;-1&beta; IL)&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x4E0E;&#x4E0D;&#x540C;&#x7684;&#x4E0B;&#x5348;&#xFF0C;LPS &#x6CBB;&#x7597; TM &#x662F;&#x96BE;&#x6CBB;&#x6027;&#x5230; NF&kappa;B &#x6FC0;&#x6D3B;&#x7F3A;&#x5C11;&#x7684; I&kappa;B&alpha; &#x7684;&#x9000;&#x5316;&#x548C;&#x7F3A;&#x4E4F;&#x708E;&#x75C7;&#x6027;&#x7EC6;&#x80DE;&#x56E0;&#x5B50;&#x5206;&#x6CCC; (IL-6&#x3001; &#x80BF;&#x7624;&#x574F;&#x6B7B;&#x56E0;&#x5B50;-&alpha;) &#x6240;&#x793A;&#x3002;&#x4E24;&#x8005;&#x5408;&#x8BA1;&#xFF0C;&#x8FD9;&#x4E9B;&#x7ED3;&#x679C;&#x8868;&#x660E;&#x8FD9;&#x4E00;&#x96BE;&#x9898;&#x7684;&#x673A;&#x5236;&#x7531;&#x54EA;&#x4E2A; TM &#x542F;&#x52A8;&#x514D;&#x75AB;&#x5E94;&#x7B54;&#x7684;&#x7EC6;&#x83CC;&#xFF0C;&#x540C;&#x65F6;&#x4E0E;&#x5B83;&#x80FD;&#x591F;&#x5BB9;&#x5FCD;&#x65B0;&#x7279;&#x8868;&#x793A;&#x5BF9;&#x53D1;&#x5C55;&#x4E2D;&#x56FD;&#x5BB6;&#x751F;&#x7CBE;&#x7EC6;&#x80DE;&#x4FDD;&#x6301;&#x777E;&#x4E38;&#x514D;&#x75AB;&#x7279;&#x6743;&#x3002;

&#x81F4;&#x80BE;&#x76C2;&#x80BE;&#x708E;&#x5927;&#x80A0;&#x6746;&#x83CC;&#x8BF1;&#x5BFC;&#x4E0D;&#x540C;&#x777E;&#x4E38;&#x548C;&#x8179;&#x8154;&#x5DE8;&#x566C;&#x7EC6;&#x80DE;&#x7684;&#x514D;&#x75AB;&#x5E94;&#x7B54;&#xFF1A; &#x777E;&#x4E38;&#x514D;&#x75AB;&#x8D66;&#x514D;&#x7684;&#x5F71;&#x54CD;&#x3002;

Infertility affects one in seven couples and ascending bacterial infections of the male genitourinary tract by Escherichia coli are an important cause of male factor infertility. Thus understanding mechanisms by which immunocompetent cells such as testicular macrophages (TM) respond to infection and how bacterial pathogens manipulate defense pathways is of importance. Whole genome expression profiling of TM and peritoneal macrophages (PM) infected with uropathogenic E. coli (UPEC) revealed major differences in regulated genes. However, a multitude of genes implicated in calcium signaling pathways was a common feature which indicated a role of calcium-dependent nuclear factor of activated T cells (NFAT) signaling. UPEC-dependent NFAT activation was confirmed in both cultured TM and in TM in an in vivo UPEC infectious rat orchitis model. Elevated expression of NFATC2-regulated anti-inflammatory cytokines was found in TM (IL-4, IL-13) and PM (IL-3, IL-4, IL-13). NFATC2 is activated by rapid influx of calcium, an activity delineated to the pore forming toxin alpha-hemolysin by bacterial mutant analysis. Alpha-hemolysin suppressed IL-6 and TNF-Î± cytokine release from PM and caused differential activation of MAP kinase and AP-1 signaling pathways in TM and PM leading to reciprocal expression of key pro-inflammatory cytokines in PM (IL-1Î±, IL-1Î², IL-6 downregulated) and TM (IL-1Î², IL-6 upregulated). In addition, unlike PM, LPS-treated TM were refractory to NFÎºB activation shown by the absence of degradation of IÎºBÎ± and lack of pro-inflammatory cytokine secretion (IL-6, TNF-Î±). Taken together, these results suggest a mechanism to the conundrum by which TM initiate immune responses to bacteria, while maintaining testicular immune privilege with its ability to tolerate neo-autoantigens expressed on developing spermatogenic cells.

Uropathogenic E. coli induce different immune response in testicular and peritoneal macrophages: implications for testicular immune privilege.

L&#x26;#39;infertilit&#xE9; touche un couple sur sept et croissant des infections bact&#xE9;riennes de l&#x26;#39;appareil g&#xE9;nito-urinaire masculin par Escherichia coli sont une cause importante de l&#x26;#39;infertilit&#xE9; masculine. Ainsi la compr&#xE9;hension des m&#xE9;canismes par lesquels les cellules immunocomp&#xE9;tentes telles que les macrophages testiculaires (TM) r&#xE9;pondent &#xE0; l&#x26;#39;infection et comment manipuler les agents pathog&#xE8;nes bact&#xE9;riens voies de d&#xE9;fense est d&#x26;#39;une importance. Tout le profilage de l&#x26;#39;expression du g&#xE9;nome des macrophages TM et p&#xE9;riton&#xE9;ale (PM) infect&#xE9;es par la bact&#xE9;rie E. coli uropathog&#xE8;nes (UPEC) a r&#xE9;v&#xE9;l&#xE9; des diff&#xE9;rences importantes dans les g&#xE8;nes r&#xE9;gul&#xE9;s. Cependant, une multitude de g&#xE8;nes impliqu&#xE9;s dans les voies de signalisation de calcium est une caract&#xE9;ristique commune qui indique un r&#xF4;le du calcium-d&#xE9;pendante du facteur nucl&#xE9;aire des lymphocytes T activ&#xE9;s (NFAT) de signalisation. Activation NFAT UPEC-d&#xE9;pendante a &#xE9;t&#xE9; confirm&#xE9;e &#xE0; la fois cultiv&#xE9;e TM et TM dans une &#xE9;tude in vivo chez le rat UPEC mod&#xE8;le orchite infectieuse. Une expression &#xE9;lev&#xE9;e d&#x26;#39;NFATC2 r&#xE9;gul&#xE9;s cytokines anti-inflammatoires a &#xE9;t&#xE9; trouv&#xE9;e dans MC (IL-4, IL-13) et PM (IL-3, IL-4, IL-13). NFATC2 est activ&#xE9; par l&#x26;#39;influx de calcium rapide, une activit&#xE9; d&#xE9;limit&#xE9;e &#xE0; la toxine porog&#xE8;ne alpha-h&#xE9;molysine par analyse bact&#xE9;rienne mutante. Alpha-h&#xE9;molysine supprim&#xE9; l&#x26;#39;IL-6 et la lib&#xE9;ration de TNF-&#x3B1; cytokine de PM et de l&#x26;#39;activation diff&#xE9;rentielle caus&#xE9; des MAP kinases et AP-1 dans les voies de signalisation TM et PM conduisant &#xE0; l&#x26;#39;expression r&#xE9;ciproque des cl&#xE9;s cytokines pro-inflammatoires dans les PM (IL-1&#x3B1;, IL -1&#x3B2;, IL-6 r&#xE9;prim&#xE9;e) et TM (IL-1&#x3B2;, IL-6 r&#xE9;gul&#xE9;s &#xE0; la hausse). En outre, contrairement &#xE0; PM, LPS-trait&#xE9;e MC &#xE9;taient r&#xE9;fractaires &#xE0; l&#x26;#39;activation NFKB montr&#xE9; par l&#x26;#39;absence de d&#xE9;gradation de I&#x3BA;B&#x3B1; et le manque de s&#xE9;cr&#xE9;tion de cytokines pro-inflammatoires (IL-6, TNF-&#x3B1;). Pris ensemble, ces r&#xE9;sultats sugg&#xE8;rent un m&#xE9;canisme pour r&#xE9;soudre l&#x26;#39;&#xE9;nigme qui TM initier des r&#xE9;ponses immunitaires &#xE0; des bact&#xE9;ries, tout en conservant le privil&#xE8;ge des testicules immunitaire avec sa capacit&#xE9; &#xE0; tol&#xE9;rer le n&#xE9;o-auto-antig&#xE8;nes exprim&#xE9;s sur le d&#xE9;veloppement de cellules spermatiques.

Uropathog&#xE8;nes E. Coli Provoquer diff&#xE9;rente de la r&#xE9;ponse immunitaire dans les macrophages testiculaires et p&#xE9;riton&#xE9;ale: Implications pour la Privil&#xE8;ge immunitaire du testicule

Unfruchtbarkeit betrifft einer von sieben Paare und aufsteigende bakterielle Infektionen der m&auml;nnlichen Urogenitalsystems von Escherichia coli sind eine wichtige Ursache f&uuml;r Unfruchtbarkeit des m&auml;nnlichen Faktor. Mechanismen von immunkompetenten Zellen so zu verstehen, wie Testikular-Makrophagen (TM) auf Infektionen zu reagieren und wie bakterielle Krankheitserreger Verteidigung Wege manipulieren ist von Bedeutung. Whole Genome Expression profiling von TM und peritonealen Makrophagen (PM) mit Uropathogenic E. Coli (UPEC) infiziert, offenbart gro&szlig;e Unterschiede in regulierter Gene. Eine Vielzahl von Genen, die in Kalzium Signalisierung Wege verwickelt war jedoch ein gemeinsames Merkmal, das Rolle des Kalzium-abh&auml;ngigen nuklearen Faktor der aktivierten T-Zellen (NFAT) Signalisierung angegeben. UPEC-abh&auml;ngige NFAT-Aktivierung wurde in beiden kultivierten TM und TM in einer in-vivo UPEC infekti&ouml;se Orchitis Rattenmodell best&auml;tigt. Erh&ouml;hte Expression von NFATC2 geregelten Anti-inflammatory Cytokines fand sich in TM (IL-4, IL-13) und PM (IL-3, IL-4, IL-13). NFATC2 wird durch raschen Zustrom von Kalzium, eine Aktivit&auml;t abgegrenzt, die Pore bilden Toxin Alpha-Hemolysin durch bakterielle mutant Analyse aktiviert. Alpha-Hemolysin IL-6 und TNF-&alpha; Cytokine Freigabe von PM unterdr&uuml;ckt und verursachte differentielle Aktivierung der MAP-Kinase und AP-1 Signalwege in TM und PM zu gegenseitiger Ausdruck der wichtigsten Pro-inflammatorische Zytokine in PM (IL-1&alpha;, IL-1&beta;, IL-6 Downregulated) und TM (IL-1&beta;, IL-6-herraufreguliert). Zus&auml;tzlich anders als PM, LPS behandelten TM waren auf NF&kappa;B-Aktivierung durch das Fehlen einer Verschlechterung der I&kappa;B&alpha; und Mangel an Pro-inflammatorische Zytokin-Sekretion (IL-6, TNF-&alpha;) gezeigt. Zusammengenommen deuten diese Ergebnisse einen Mechanismus, um die R&auml;tsel durch welche TM initiieren Immunantworten auf Bakterien, unter Beibehaltung der testikul&auml;ren immun-Privileg mit seiner F&auml;higkeit, Neo-Autoantigene ausgedr&uuml;ckt auf die Entwicklung von spermatogenic Zellen zu tolerieren.

Uropathogenic E. coli veranlassen unterschiedliche Immunantwort bei Hoden- und peritonealen Makrophagen: Implikationen f&uuml;r testikul&auml;re immun-Privileg.

Infertilit&agrave; colpisce uno su sette coppie e crescente di infezioni batteriche del tratto genito-urinario maschile di Escherichia coli sono un&#39;importante causa di infertilit&agrave; fattore maschile. Cos&igrave; comprendere meccanismi da cui le cellule immunitarie come i macrofagi testicolari (TM) rispondono alle infezioni e come agenti patogeni batterici manipolare percorsi di difesa &egrave; di importanza. Intero genoma delineamento di espressione della TM e macrofagi peritoneali (PM) infettati con uropathogenic e. coli (UPEC) ha rivelato importanti differenze nei geni. Tuttavia, una moltitudine di geni implicati nelle vie di segnalazione di calcio era una caratteristica comune che ha indicato un ruolo di calcio-dipendente fattore nucleare delle cellule T attivate (NFAT) di segnalazione. Attivazione NFAT UPEC-dipendente &egrave; stata confermata in entrambe TM colta e TM in un modello di orchite infettive ratto UPEC in vivo. Elevata espressione di citochine anti-infiammatorie NFATC2 regolamentati &egrave; stato trovato in TM (IL-4, IL-13) e PM (IL-3, IL-4, IL-13). NFATC2 &egrave; attivata dal rapido afflusso di calcio, un&#39;attivit&agrave; delimitata per il poro formante tossina alfa-emolisina da analisi di mutanti batterici. Alfa-emolisina soppresso il rilascio di citochine IL-6 e TNF-&alpha; da PM e causato differenziale attivazione della chinasi di mappa e AP-1 signaling pathways in TM e PM che porta alla reciproca espressione di citochine pro-infiammatorie chiave in PM (IL 1&alpha;, IL-1 &beta;, IL-6 downregolata) e TM (IL-1 &beta;, IL-6 sovraregolati). Inoltre, a differenza dei PM, TM LPS-trattati erano refrattari all&#39;attivazione di NF&kappa;B dimostrato dall&#39;assenza di degradazione di I&kappa;B&alpha; e mancanza di secrezione di citochine pro-infiammatorie (IL-6, TNF-&alpha;). Presi insieme, questi risultati suggeriscono un meccanismo per l&#39;enigma di cui risposte immunitarie initiate TM a batteri, pur mantenendo il privilegio immunitario testicolare con la sua capacit&agrave; di tollerare neo-autoantigeni espressi sullo sviluppo di cellule spermatogenic.

Uropathogenic E. coli inducono risposta immunitaria differente nei macrofagi peritoneali e testicolare: implicazioni per il privilegio immunitario testicolare.

&#x4E0D;&#x598A;&#x306F;&#x3001;7&#x7D44;&#x306E;1&#x3064;&#x306B;&#x5F71;&#x97FF;&#x3092;&#x4E0E;&#x3048;&#x3001;&#x5927;&#x8178;&#x83CC;&#x306B;&#x3088;&#x308B;&#x7537;&#x6027;&#x306E;&#x6CCC;&#x5C3F;&#x751F;&#x6B96;&#x8DEF;&#x306E;&#x7D30;&#x83CC;&#x611F;&#x67D3;&#x3092;&#x6607;&#x9806;&#x3068;&#x7537;&#x6027;&#x56E0;&#x5B50;&#x306E;&#x4E0D;&#x598A;&#x306E;&#x91CD;&#x8981;&#x306A;&#x539F;&#x56E0;&#x3068;&#x306A;&#x3063;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;&#x305D;&#x306E;&#x3088;&#x3046;&#x306A;&#x7CBE;&#x5DE3;&#x30DE;&#x30AF;&#x30ED;&#x30D5;&#x30A1;&#x30FC;&#x30B8;&#x306A;&#x3069;&#x306E;&#x514D;&#x75AB;&#x62C5;&#x5F53;&#x7D30;&#x80DE;&#xFF08;TM&#xFF09;&#x306F;&#x3001;&#x611F;&#x67D3;&#x306B;&#x5FDC;&#x7B54;&#x3057;&#x3066;&#x3001;&#x3069;&#x306E;&#x3088;&#x3046;&#x306B;&#x7D30;&#x83CC;&#x306E;&#x75C5;&#x539F;&#x4F53;&#x306E;&#x9632;&#x5FA1;&#x7D4C;&#x8DEF;&#x3092;&#x64CD;&#x4F5C;&#x3059;&#x308B;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x3092;&#x7406;&#x89E3;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x91CD;&#x8981;&#x3067;&#x3042;&#x308B;&#x3002;&#x5C3F;&#x8DEF;&#x75C5;&#x539F;&#x6027;&#x5927;&#x8178;&#x83CC;&#xFF08;UPEC&#xFF09;&#x306B;&#x611F;&#x67D3;&#x3057;&#x305F;TM&#x304A;&#x3088;&#x3073;&#x8179;&#x8154;&#x30DE;&#x30AF;&#x30ED;&#x30D5;&#x30A1;&#x30FC;&#x30B8;&#xFF08;PM&#xFF09;&#x306E;&#x5168;&#x30B2;&#x30CE;&#x30E0;&#x767A;&#x73FE;&#x30D7;&#x30ED;&#x30D5;&#x30A1;&#x30A4;&#x30EA;&#x30F3;&#x30B0;&#x306F;&#x3001;&#x8ABF;&#x7BC0;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x4E3B;&#x306A;&#x9055;&#x3044;&#x3092;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x305F;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;&#x30AB;&#x30EB;&#x30B7;&#x30A6;&#x30E0;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x7D4C;&#x8DEF;&#x306B;&#x95A2;&#x4E0E;&#x3059;&#x308B;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x591A;&#x304F;&#x306F;&#x3001;&#x6D3B;&#x6027;&#x5316;T&#x7D30;&#x80DE;&#x306E;&#x30AB;&#x30EB;&#x30B7;&#x30A6;&#x30E0;&#x4F9D;&#x5B58;&#x6027;&#x306E;&#x6838;&#x56E0;&#x5B50;&#xFF08;NFAT&#xFF09;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x306E;&#x5F79;&#x5272;&#x3092;&#x793A;&#x3057;&#x305F;&#x5171;&#x901A;&#x306E;&#x7279;&#x5FB4;&#x3067;&#x3042;&#x3063;&#x305F;&#x3002; UPEC&#x4F9D;&#x5B58;NFAT&#x306E;&#x6D3B;&#x6027;&#x5316;&#x306F;&#x3001;in vivo UPEC&#x611F;&#x67D3;&#x30E9;&#x30C3;&#x30C8;&#x306E;&#x7CBE;&#x5DE3;&#x708E;&#x30E2;&#x30C7;&#x30EB;&#x306E;&#x4E21;&#x65B9;&#x3067;&#x57F9;&#x990A;&#x3055;&#x308C;&#x305F;TM&#x3084;TM&#x3067;&#x78BA;&#x8A8D;&#x3055;&#x308C;&#x305F;&#x3002; NFATC2&#x8ABF;&#x7BC0;&#x6297;&#x708E;&#x75C7;&#x6027;&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;&#x306E;&#x767A;&#x73FE;&#x4E0A;&#x6607;&#x306F;&#x3001;TM&#xFF08;IL-4&#x3001;IL-13&#xFF09;&#x304A;&#x3088;&#x3073;PM&#xFF08;IL-3&#x3001;IL-4&#x3001;IL-13&#xFF09;&#x306B;&#x8A8D;&#x3081;&#x3089;&#x308C;&#x305F;&#x3002; NFATC2&#x306F;&#x3001;&#x30AB;&#x30EB;&#x30B7;&#x30A6;&#x30E0;&#x306E;&#x6025;&#x6FC0;&#x306A;&#x6D41;&#x5165;&#x3001;&#x7D30;&#x83CC;&#x306E;&#x5909;&#x7570;&#x4F53;&#x89E3;&#x6790;&#x306B;&#x3088;&#x308A;&#x7D30;&#x5B54;&#x5F62;&#x6210;&#x6BD2;&#x7D20;&#x3B1;-&#x6EB6;&#x8840;&#x7D20;&#x306B;&#x7DDA;&#x5F15;&#x304D;&#x6D3B;&#x52D5;&#x306B;&#x3088;&#x3063;&#x3066;&#x6D3B;&#x6027;&#x5316;&#x3055;&#x308C;&#x308B;&#x3002; &#x3B1;-&#x6EB6;&#x8840;&#x3092;&#x6291;&#x5236;&#x3057;IL-6&#x304A;&#x3088;&#x3073;TNF-&#x3B1;PM&#x304B;&#x3089;&#x306E;&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;&#x653E;&#x51FA;&#x3068;MAP&#x30AD;&#x30CA;&#x30FC;&#x30BC;&#x3068;PM&#xFF08;IL-1&#x3B1;&#x3001;IL&#x306E;&#x4E3B;&#x8981;&#x306A;&#x708E;&#x75C7;&#x6027;&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;&#x306E;&#x9006;&#x6570;&#x306E;&#x767A;&#x73FE;&#x306B;&#x3064;&#x306A;&#x304C;&#x308B;TM&#x304A;&#x3088;&#x3073;PM&#x306E;AP-1&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x7D4C;&#x8DEF;&#x306E;&#x539F;&#x56E0;&#x3068;&#x306A;&#x3063;&#x305F;&#x5DEE;&#x52D5;&#x306E;&#x6D3B;&#x6027;&#x5316;-1&#x3B2;&#x3001;IL-6&#x30C0;&#x30A6;&#x30F3;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30C8;&#xFF09;&#x3068;TM&#xFF08;IL-1&#x3B2;&#x3001;IL-6&#x30A2;&#x30C3;&#x30D7;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30C8;&#x3055;&#x308C;&#x308B;&#xFF09;&#x3002;&#x3055;&#x3089;&#x306B;&#x3001;PM&#x3068;&#x306F;&#x7570;&#x306A;&#x308A;&#x3001;LPS&#x51E6;&#x7406;TM&#x306F;&#x3001;I&#x3BA;B&#x3B1;&#x306E;&#x5206;&#x89E3;&#x306E;&#x6709;&#x7121;&#x3068;&#x708E;&#x75C7;&#x6027;&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;&#x5206;&#x6CCC;&#x306E;&#x6B20;&#x5982;&#xFF08;IL-6&#x3001;TNF-&#x3B1;&#xFF09;&#x3067;&#x8868;&#x3055;&#x308C;&#x308B;NF&#x3BA;B&#x306E;&#x6D3B;&#x6027;&#x5316;&#x200B;&#x200B;&#x306B;&#x96E3;&#x6CBB;&#x6027;&#x3067;&#x3042;&#x3063;&#x305F;&#x3002;&#x4E00;&#x7DD2;&#x306B;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x7D50;&#x679C;&#x306F;&#x3001;&#x7CBE;&#x5B50;&#x5F62;&#x6210;&#x7D30;&#x80DE;&#x3092;&#x958B;&#x767A;&#x3059;&#x308B;&#x4E0A;&#x3067;&#x767A;&#x73FE;&#x30CD;&#x30AA;&#x6297;&#x539F;&#x3092;&#x8A31;&#x5BB9;&#x3059;&#x308B;&#x80FD;&#x529B;&#x3068;&#x7CBE;&#x5DE3;&#x306E;&#x514D;&#x75AB;&#x7279;&#x6A29;&#x3092;&#x7DAD;&#x6301;&#x3057;&#x306A;&#x304C;&#x3089;&#x3001;TM&#x306F;&#x3001;&#x7D30;&#x83CC;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x514D;&#x75AB;&#x5FDC;&#x7B54;&#x3092;&#x958B;&#x59CB;&#x3057;&#x305F;&#x3053;&#x3068;&#x3067;&#x96E3;&#x554F;&#x306B;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;

&#x7CBE;&#x5DE3;&#x306E;&#x514D;&#x75AB;&#x7279;&#x6A29;&#x306E;&#x305F;&#x3081;&#x306E;&#x542B;&#x610F;&#xFF1A;&#x5C3F;&#x8DEF;&#x75C5;&#x539F;&#x6027;&#x5927;&#x8178;&#x83CC;&#x306F;&#x3001;&#x7CBE;&#x5DE3;&#x3068;&#x8179;&#x8154;&#x30DE;&#x30AF;&#x30ED;&#x30D5;&#x30A1;&#x30FC;&#x30B8;&#x306E;&#x7570;&#x306A;&#x308B;&#x514D;&#x200B;&#x200B;&#x75AB;&#x5FDC;&#x7B54;&#x3092;&#x8A98;&#x767A;&#x3059;&#x308B;

&#xBD88; &#xC784;&#xC5D0; &#xC601;&#xD5A5;&#xC744; &#xBBF8;&#xCE58;&#xB294; 7 &#xD55C; &#xCEE4;&#xD50C;&#xACFC; Escherichia &#xC5EC; &#xB0A8;&#xC131; &#xBE44;&#xB1E8; &#xAD00;&#xC758; &#xC138;&#xADE0; &#xAC10;&#xC5FC;&#xC744; &#xC624;&#xB984;&#xCC28;&#xC21C; &#xB300;&#xC7A5;&#xADE0;&#xC740; &#xB0A8;&#xC131; &#xC694;&#xC778; &#xBD88; &#xC784;&#xC758; &#xC911;&#xC694; &#xD55C; &#xC6D0;&#xC778;. &#xACE0;&#xD658; &#xC138;&#xD3EC; (TM) &#xC751;&#xB2F5; &#xAC10;&#xC5FC; &#xB4F1; &#xC138;&#xADE0; &#xBCD1;&#xC6D0; &#xADE0; &#xBC29;&#xC5B4; &#xACBD;&#xB85C; &#xC870;&#xC791; &#xD558;&#xB294; &#xBC29;&#xBC95;&#xC5D0; &#xB530;&#xB77C;&#xC11C; immunocompetent &#xC140;&#xC5D0; &#xC758;&#xD574; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xC774;&#xD574; &#xD558;&#xB294; &#xAC83;&#xC740; &#xC911;&#xC694;&#xC131; &#xC774;&#xB2E4;. &#xC804;&#xCCB4; &#xAC8C;&#xB188; &#xC2DD;&#xC758; &#xD504;&#xB85C; &#xD30C;&#xC77C;&#xB9C1; TM &#xBC0F; &#xBCF5; &#xB9C9; &#xB300; &#xC2DD; &#xC138;&#xD3EC; (&#xC624;&#xD6C4;)&#xC5D0; &#xAC10;&#xC5FC; &#xB41C; &#xB300;&#xC7A5;&#xADE0; (UPEC) uropathogenic &#xB808; &#xADE4; &#xB808;&#xC774;&#xD2B8; &#xB41C; &#xC720;&#xC804;&#xC790;&#xC758; &#xC8FC;&#xC694; &#xCC28;&#xC774; &#xACF5;&#xAC1C; &#xD588;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, &#xB2E4;&#xC591; &#xD55C; &#xCE7C;&#xC298; &#xC2E0;&#xD638; &#xACBD;&#xB85C;&#xC5D0; &#xB0B4;&#xD3EC; &#xB41C; &#xC720;&#xC804;&#xC790;&#xB294; &#xD65C;&#xC131;&#xD654; &#xB41C; T &#xC138;&#xD3EC; (NFAT) &#xC2DC;&#xADF8;&#xB110;&#xB9C1;&#xC758; &#xCE7C;&#xC298; &#xC885;&#xC18D; &#xD575; &#xC694;&#xC18C;&#xC758; &#xC5ED;&#xD560;&#xC744; &#xD45C;&#xC2DC; &#xD558;&#xB294; &#xC77C;&#xBC18;&#xC801;&#xC778; &#xAE30;&#xB2A5;. UPEC &#xC885;&#xC18D; NFAT &#xD65C;&#xC131;&#xD654; vivo&#xC5D0;&#xC11C; UPEC &#xAC10;&#xC5FC; &#xC950; orchitis &#xBAA8;&#xB378;&#xC5D0; &#xB450; &#xAD50;&#xC591;&#xB41C; TM &#xBC0F; TM&#xC73C;&#xB85C; &#xD655;&#xC778; &#xB410;&#xB2E4;. NFATC2 &#xADDC;&#xC81C; &#xD56D; &#xC5FC;&#xC99D; &#xC131; cytokines&#xC758; &#xB192;&#xC740; &#xC2DD; TM (IL-4, IL-13)&#xC5D0;&#xC11C; &#xBC1C;&#xACAC; &#xB41C; &#xC2DC; (IL-3, &#xC77C;&#xB9AC;&#xB178;&#xC774;-4, IL-13). NFATC2 &#xCE7C;&#xC298;, &#xC138;&#xADE0; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xBD84;&#xC11D; &#xD558;&#xB294; &#xAE30; &#xACF5; &#xD615;&#xC131; &#xB3C5; &#xC18C; &#xC54C;&#xD30C;-hemolysin delineated &#xD65C;&#xB3D9;&#xC758; &#xAE09;&#xC18D; &#xD55C; &#xC720;&#xC785;&#xC5D0; &#xC758;&#xD574; &#xD65C;&#xC131;&#xD654; &#xB429;&#xB2C8;&#xB2E4;. &#xC54C;&#xD30C;-hemolysin &#xC624;&#xD6C4;&#xC5D0;&#xC11C; &#xC77C;&#xB9AC;&#xB178;&#xC774;-6&#xC640; TNF-&alpha; cytokine &#xB9B4;&#xB9AC;&#xC2A4;&#xB97C; &#xC5B5;&#xC555; &#xD558; &#xACE0; TM &#xBC0F; &#xC624;&#xD6C4; &#xC624;&#xD6C4; (IL 1&alpha;, IL 1&beta;, &#xC77C;&#xB9AC;&#xB178;&#xC774;-6 downregulated)&#xC5D0;&#xC11C; &#xC8FC;&#xC694; &#xD504;&#xB85C; &#xC5FC;&#xC99D; &#xC131; cytokines&#xC758; &#xC0C1;&#xD638; &#xC2DD; &#xC120;&#xB3C4; &#xC9C0;&#xB3C4; &#xD0A4; &#xB2C8; &#xC544; &#xC81C; &#xBC0F; AP-1 &#xC2E0;&#xD638; &#xD1B5;&#xB85C;&#xC758; &#xCC28;&#xB3D9; &#xD65C;&#xC131;&#xD654; &#xBC1C;&#xC0DD; &#xBC0F; TM (IL 1&beta;, &#xC77C;&#xB9AC;&#xB178;&#xC774;-6 upregulated). &#xB610;&#xD55C;, &#xC624;&#xD6C4;, &#xB2EC;&#xB9AC; LPS &#xCC98;&#xB9AC; TM NF&kappa;B &#xC815;&#xD488; &#xC778;&#xC99D; I&kappa;B&alpha;&#xC758; &#xC800;&#xD558;&#xC640; &#xD504;&#xB85C;-&#xC5FC;&#xC99D; &#xC131; cytokine &#xBD84; &#xBE44; (IL 6, TNF-&alpha;)&#xC758; &#xBD80;&#xC871;&#xC758; &#xBD80;&#xC7AC;&#xC5D0; &#xC758;&#xD574; &#xD45C;&#xC2DC; &#xB41C; &#xB0B4; &#xD654; &#xD588;&#xB2E4;. &#xD568;&#xAED8; &#xCC0D;&#xC740;, &#xC774;&#xB7EC;&#xD55C; &#xACB0;&#xACFC; &#xC81C;&#xC548; &#xC218;&#xC218;&#xAED8;&#xB07C;&#xB97C; &#xBA54;&#xCEE4;&#xB2C8;&#xC998; &#xBC15;&#xD14C;&#xB9AC;&#xC544;&#xB294; TM &#xC2DC;&#xC791; &#xBA74;&#xC5ED; &#xC751;&#xB2F5;&#xC5D0; &#xC758;&#xD574; &#xC6A9;&#xB0A9; &#xB124;&#xC624; autoantigens spermatogenic &#xC140; &#xAC1C;&#xBC1C;&#xC5D0; &#xD45C;&#xD604; &#xD558;&#xB294; &#xB2A5;&#xB825;&#xC73C;&#xB85C; &#xACE0;&#xD658; &#xBA74;&#xC5ED; &#xD2B9;&#xAD8C;&#xC744; &#xC720;&#xC9C0; &#xD558;&#xBA74;&#xC11C;.

Uropathogenic &#xB300;&#xC7A5;&#xADE0; &#xACE0;&#xD658;&#xACFC; &#xBCF5; &#xB9C9; &#xC138;&#xD3EC;&#xC5D0;&#xC11C; &#xC11C;&#xB85C; &#xB2E4;&#xB978; &#xBA74;&#xC5ED; &#xBC18;&#xC751; &#xC720;&#xB3C4;: &#xACE0;&#xD658; &#xBA74;&#xC5ED; &#xD2B9;&#xAD8C;&#xC5D0; &#xB300; &#xD55C; &#xC758;&#xBBF8;.

La infertilidad afecta a uno de cada siete parejas y subiendo las infecciones bacterianas del tracto genitourinario masculino por Escherichia coli es una causa importante de infertilidad por factor masculino. As&#xED; comprensi&#xF3;n de los mecanismos por los cuales las c&#xE9;lulas inmunocompetentes como los macr&#xF3;fagos testiculares (TM) responden a la infecci&#xF3;n y c&#xF3;mo los pat&#xF3;genos bacterianos manipular las v&#xED;as de defensa es de importancia. Todo el perfil de la expresi&#xF3;n del genoma de los macr&#xF3;fagos TM y peritoneal (PM) infectados con E. coli uropathogenic (UPEC) revel&#xF3; importantes diferencias en los genes regulados. Sin embargo, un gran n&#xFA;mero de genes implicados en las v&#xED;as de se&#xF1;alizaci&#xF3;n del calcio era una caracter&#xED;stica com&#xFA;n, que indica un papel de calcio dependiente de factor nuclear de c&#xE9;lulas T activadas (NFAT) de se&#xF1;alizaci&#xF3;n. UPEC-dependiente de la activaci&#xF3;n de NFAT se confirm&#xF3;, tanto en cultivo como en TM TM en un estudio in vivo UPEC modelo de orquitis infecciosa de la rata. Elevada expresi&#xF3;n de NFATc2 regulados citocinas anti-inflamatorias se encontr&#xF3; en TM (IL-4, IL-13) y PM (IL-3, IL-4, IL-13). NFATc2 es activado por la r&#xE1;pida afluencia de calcio, una actividad delimitada a la toxina formador de poros alfa-hemolisina por an&#xE1;lisis de mutantes bacteriana. El alfa-hemolisina supresi&#xF3;n de IL-6 y TNF-&#x3B1; liberaci&#xF3;n de citocinas y la activaci&#xF3;n de la PM caus&#xF3; diferencial de la MAP quinasa y AP-1 v&#xED;as de se&#xF1;alizaci&#xF3;n en TM y AM que conduce a la expresi&#xF3;n rec&#xED;proca de las principales citoquinas pro-inflamatorias en PM (IL-1&#x3B1;, IL -1&#x3B2;, IL-6 downregulated) y TM (IL-1&#x3B2;, IL-6 upregulated). Adem&#xE1;s, a diferencia de AM, LPS-tratada TM fueron refractarios a la activaci&#xF3;n NFkB se muestra por la ausencia de degradaci&#xF3;n de I&#x3BA;B&#x3B1; y la falta de secreci&#xF3;n de citoquinas pro-inflamatorias (IL-6, TNF-&#x3B1;). En conjunto, estos resultados sugieren un mecanismo para el enigma por el cual TM iniciar la respuesta inmune a las bacterias, manteniendo al mismo tiempo el privilegio inmune testicular con su capacidad de tolerar neo-autoant&#xED;genos expresados &#x200B;&#x200B;en el desarrollo de las c&#xE9;lulas de espermatog&#xE9;nesis.

Escherichia coli uropat&#xF3;gena inducir la respuesta inmune diferente en los macr&#xF3;fagos testiculares y peritoneal: Implicaciones para el privilegio inmune de test&#xED;culo

Male infertility is a frequent medical condition, compromising approximately one in twenty men, with infections of the reproductive tract constituting a major etiological factor. Bacterial epididymo-orchitis results in acute inflammation most often caused by ascending canalicular infections from the urethra via the continuous male excurrent ductal system. Uropathogenic Escherichia coli (UPEC) represent a relevant pathogen in urogenital tract infections. To explore how bacteria can cause damage and cell loss and thus impair fertility, an in vivo epididymo-orchitis model was employed in rats by injecting UPEC strain CFT073 into the vas deference in close proximity to the epididymis. Seven days post infection bacteria were found predominantly in the testicular interstitial space. UPEC infection resulted in severe impairment of spermatogenesis by germ cell loss, damage of testicular somatic cells, a decrease in sperm numbers and a significant increase in TUNEL (+) cells. Activation of caspase-8 (extrinsic apoptotic pathway), caspase-3/-6 (intrinsic apoptotic pathway), caspase-1 (pyroptosis pathway) and the presence of 180 bp DNA fragments, all of which serve as indicators of the classical apoptotic pathway, were not observed in infected testis. Notably, electron microscopical examination revealed degenerative features of Sertoli cells (SC) in UPEC infected testis. Furthermore, the passive release of high mobility group protein B1 (HMGB1), as an indication of necrosis, was observed in vivo in infected testis. Thus, necrosis appears to be the dominant cell death pathway in UPEC infected testis. Substantial necrotic changes seen in Sertoli cells will contribute to impaired spermatogenesis by loss of function in supporting the dependent germ cells.

Necrosis is the dominant cell death pathway in uropathogenic Escherichia coli elicited epididymo-orchitis and is responsible for damage of rat testis.

Uropathogenic Escherichia coli (UPEC)-associated epididymitis is commonly diagnosed in outpatient settings. Although the infection can be successfully cleared using antimicrobial medications, 40% of patients unexplainably show persistent impaired semen parameters even after treatment. Our aim was to investigate whether pathogenic UPEC and its associated virulence factor hemolysin (hlyA) perturb the structural and functional integrity of both the epididymis and sperm, actions that may be responsible for the observed impairment and possibly a reduction of fertilization capabilities. Semen collected from patients diagnosed with E. coli-only related epididymitis showed that sperm counts were low 14 days postantimicrobial treatment regardless of hlyA status. At Day 84 following treatment, hlyA production correlated with approximately 4-fold lower sperm concentrations than in men with hlyA-negative strains. In vivo experiments with the hlyA-producing UPEC CFT073 strain in a murine epididymitis model showed that just 3 days postinfection, structural damage to the epididymis (epithelial damage, leukocyte infiltration, and edema formation) was present. This was more severe in UPEC CFT073 compared to nonpathogenic E. coli (NPEC 470) infection. Moreover, pathogenic UPEC strains prematurely activated the acrosome in vivo and in vitro. Raman microspectroscopy revealed that UPEC CFT073 undermined sperm integrity by inducing nuclear DNA damage. Consistent with these observations, the in vitro fertilization capability of hlyA-treated mouse sperm was completely abolished, although sperm were motile. These findings provide new insights into understanding the possible processes underlying clinical manifestations of acute epididymitis.

Structural and functional integrity of spermatozoa is compromised as a consequence of acute uropathogenic E. coli-associated epididymitis.

Infectious epididymitis in men, a frequent entity in urological outpatient settings, is commonly caused by bacteria originating from the anal region ascending the genitourinary tract. One of the most prevalent pathogens associated with epididymitis is Escherichia coli. In our previous study, we showed that semen quality is compromised in men following epididymitis associated with specific E. coli pathovars. Thus, our aim was to investigate possible differences in immune responses elicited during epididymitis following infection with the uropathogenic E. coli (UPEC) strain CFT073 and the nonpathogenic enteric E. coli (NPEC) strain 470. Employing an in vivo experimental epididymitis model, C57BL/6 mice were infected with UPEC CFT073, NPEC 470, or phosphate-buffered saline (PBS) as a sham control for up to 7 days. After infection with NPEC 470, the expression of proinflammatory cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha in the epididymis was significantly increased. Conversely, UPEC CFT073-challenged mice displayed inflammatory gene expression at levels comparable to sham PBS-treated animals. Moreover, by day 7 only NPEC-infected animals showed activation of adaptive immunity evident by a substantial influx of CD3+ and F4/80+ cells in the epididymal interstitium. This correlated with enhanced production of Th1-associated cytokines IL-2 and gamma interferon (IFN-γ). Furthermore, splenocytes isolated from UPEC-infected mice exhibited diminished T-cell responses with significantly reduced secretion of IL-2 and IFN-γ in contrast to NPEC-infected animals. Overall, these findings provide new insights into understanding pathogen-specific modulation of host immunity during acute phases of epididymitis, which may influence severity of disease and clinical outcomes.

Uropathogenic Escherichia coli modulates innate immunity to suppress Th1-mediated inflammatory responses during infectious epididymitis.

During spermiogenesis, haploid spermatids undergo extensive chromatin remodeling events in which histones are successively replaced by more basic protamines to generate highly compacted chromatin. Here we show for the first time that H3K79 methylation is a conserved feature preceding the histone-to-protamine transition in Drosophila melanogaster and rat. During Drosophila spermatogenesis, the Dot1-like methyltransferase Grappa (Gpp) is primarily expressed in canoe stage nuclei. The corresponding H3K79 methylation is a histone modification that precedes the histone-to-protamine transition and correlates with histone H4 hyperacetylation. When acetylation was inhibited in cultured Drosophila testes, nuclei were smaller and chromatin was compact, Gpp was little synthesized, H3K79 methylation was strongly reduced, and protamines were not synthesized. The Gpp isoform Gpp-D has a unique C-terminus, and Gpp is essential for full fertility. In rat, H3K79 methylation also correlates with H4 hyperacetylation but not with active RNA polymerase II, which might point towards a conserved function in chromatin remodeling during the histone-to-protamine transition in both Drosophila and rat.

H3K79 methylation: a new conserved mark that accompanies H4 hyperacetylation prior to histone-to-protamine transition in Drosophila and rat.

Does high mobility group box protein 1 (HMGB1) regulate inflammatory reactions in a rat model of experimental autoimmune orchitis (EAO)?

Targeting high mobility group box protein 1 ameliorates testicular inflammation in experimental autoimmune orchitis.

Previous studies demonstrated a strong association between low androgen levels and reduced capacity to mount an inflammatory response. However, the mechanisms underlying these observations are largely not understood.

Influence of Testosterone on Inflammatory Response in Testicular Cells and Expression of Transcription Factor Foxp3 in T Cells.

Spermatogenic cells express cell-specific molecules with the potential to be seen as "foreign" by the immune system. Owing to the time difference between their appearance in puberty and the editing of the lymphocyte repertoire around birth, local adaptations of the immune system coined immune privilege are required to confer protection from autoattack. Testicular macrophages (TM) play an important role in maintaining testicular immune privilege and display reduced proinflammatory capacity compared with other macrophages. However, the molecular mechanism underlying this macrophage phenotype remained elusive. We demonstrate that TM have a lower constitutive expression of TLR pathway-specific genes compared with peritoneal macrophages. Moreover, in TM stimulated with LPS, the NF-κB signaling pathway is blocked due to lack of IκBα ubiquitination and, hence, degradation. Instead, challenge of TM with LPS or polyinosinic-polycytidylic acid induces MAPK, AP-1, and CREB signaling pathways, which leads to production of proinflammatory cytokines such as TNF-α, although at much lower levels than in peritoneal macrophages. Pretreatment of TM with inhibitors for MAPKs p38 and ERK1/2 suppresses activation of AP-1 and CREB signaling pathways and attenuates LPS-induced TNF-α and IL-10 secretion. High levels of IL-10 production and activation of STAT3 by LPS stimulation in TM indicate a regulatory macrophage phenotype. Our results suggest that TM maintain testicular immune privilege by inhibiting NF-κB signaling through impairment of IκBα ubiquitination and a general reduction of TLR cascade gene expression. However, TM do maintain some capacity for innate immune responses through AP-1 and CREB signaling pathways.

Differential activation of inflammatory pathways in testicular macrophages provides a rationale for their subdued inflammatory capacity.

Urinary tract infections caused by uropathogenic Escherichia coli (UPEC) pathovars belong to the most frequent infections in human. It is well established that UPEC can subvert innate immune responses, but the role of UPEC in interfering with host cell death pathways is not known. Here, we show that UPEC abrogates activation of the host cell prosurvival protein kinase B signaling pathway, which results in the activation of mammalian forkhead box O (FOXO) transcription factors. Although FOXOs were localized in the nucleus and showed increased DNA-binding activity, no change in the expression levels of FOXO target genes were observed. UPEC can suppress BIM expression induced by LY249002, which results in attenuation of caspase 3 activation and blockage of apoptosis. Mechanistically, BIM expression appears to be epigenetically silenced by a decrease in histone 4 acetylation at the BIM promoter site. Taken together, these results suggest that UPEC can epigenetically silence BIM expression, a molecular switch that prevents apoptosis.

Sudhanshu Bhushan

Institut für Anatomie und Zellbiologie

Justus-Liebig-Universität Gießen

Isolation of Sertoli Cells and Peritubular Cells from Rat Testes