induction-murine-intestinal-inflammation-adoptive-transfer-effector

Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4<sup>+</sup>CD45RB<sup>high</sup> T Cells into Immunodeficient Mice

There are many different animal models available for studying the pathogenesis of human inflammatory bowel diseases (IBD), each with its own advantages ...

University of North Carolina at Chapel Hill

Absence of transforming growth factor-beta (TGF-beta) signaling to T cells in mice results in an increase in T cell numbers, an activated CD44 high, CD69-, CD25- T cell phenotype and a T cell-mediated injury to many organs. It is not known if such T cell activation in the absence of TGF-beta signaling is spontaneous or due to aberrant T cell responses to a physiological stimulus. We used adoptive transfer of CD8+ T cells from mice double transgenic for the OT-1 TCR and the TGF-beta1-dominant negative transgene [OT-dominant-negative receptor (DNR)] to investigate the role of TGF-beta in regulating CD8+ T cell activation in vivo. The activation and expansion of single-transgenic OT and double-transgenic OT-DNR cells to oral antigens, high-affinity and low-affinity peptides were indistinguishable. Activation with high-affinity peptide and CFA however resulted in greater expansion of OT-DNR cells in comparison to OT cells. Low-affinity peptide and adjuvant did not result in OT cell activation or expansion but results in up-regulation of CD44 on OT-DNR cells. These data show that TGF-beta functions in vivo to limit the scale of CD8+ T cell expansion after high-affinity peptide-MHC interactions. TGF-beta also limits T cell activation to the highest affinity peptide-MHC interactions. The increase in T cell number and activation present in TGF-beta-deficient and TGF-beta DNR-expressing mice may be due to the loss of these two phenomena.

TGF-beta signaling regulates CD8+ T cell responses to high- and low-affinity TCR interactions.

IL-23 regulation is a central event in the pathogenesis of the inflammatory bowel diseases. We demonstrate that IFN-gamma has anti-inflammatory properties in the initiation phase of IL-23-mediated experimental colitis. IFN-gamma attenuates LPS-mediated IL-23 expression in murine macrophages. Mechanistically, IFN-gamma inhibits Il23a promoter activation through altering NF-kappaB binding and histone modification. Moreover, intestinal inflammation is inhibited by IFN-gamma signaling through attenuation of Il23a gene expression. In germ-free wild-type mice colonized with enteric microbiota, inhibition of colonic Il23a temporally correlates with induction of IFN-gamma. IFN-gammaR1/IL-10 double-deficient mice demonstrate markedly increased colonic inflammation and IL23a expression compared with those of IL-10(-/-) mice. Colonic CD11b(+) cells are the primary source of IL-23 and a target for IFN-gamma. This study describes an important anti-inflammatory role for IFN-gamma through inhibition of IL-23. Converging genetic and functional findings suggest that IL-23 and IFN-gamma are important pathogenic molecules in human inflammatory bowel disease.

Cutting edge: IFN-gamma is a negative regulator of IL-23 in murine macrophages and experimental colitis.

Innate immune responses are crucial for host defense against pathogens but need to be tightly regulated to prevent chronic inflammation. Initial characterization of mice with a targeted inactivating mutation in the p110δ subunit of phosphoinositide 3-kinase (PI3K p110δ(D910A/D910A)) revealed defects in B- and T-cell signaling and chronic colitis. Here, we further characterize features of inflammatory bowel diseases in these mice and investigate underlying innate immune defects.

Altered macrophage function contributes to colitis in mice defective in the phosphoinositide-3 kinase subunit p110δ.

The purpose of this review is to highlight macrophages as central mediators of intestinal immune homeostasis and inflammation.

The role of the macrophage in sentinel responses in intestinal immunity.

We have demonstrated previously that IFN-γ plays a protective role in the initiation of chronic intestinal inflammation through attenuation of Toll-like receptor-mediated IL-23 induction in macrophages. Here, an interferon-stimulated response element (ISRE) is identified in a region of conserved nucleotide sequences in the Il23a promoter. This ISRE mediated, in part, Il23a promoter induction by LPS and inhibition of LPS-induced activity by IFN-γ. LPS and IFN-γ recruit interferon regulatory factors (IRFs) to the Il23a ISRE in murine bone marrow-derived macrophages (BMMs). Functionally, IRF-1 is a negative regulator of Il23a in LPS-stimulated BMMs. IRF-1(-/-) BMMs demonstrated enhanced LPS-induced Il23a expression compared with WT BMMs. Moreover, IRF-1 deficiency resulted in prolonged occupancy of RelA on the Il23a promoter. Consequently, IRF-1(-/-) mice were more susceptible to colonic injury by trinitrobenzenesulfonic acid, and IL-10/IRF-1 double-deficient (IL-10/IRF-1(-/-)) mice demonstrated more severe colonic inflammation compared with IL-10(-/-) mice. The severity of colitis in both models correlated with increased colonic IL-23. CD11b(+) lamina propria mononuclear cells, comprising predominantly macrophages, were identified as the major source of IL-23 in colitis-prone mice. Basal and heat-killed Escherichia coli-stimulated levels of Il23a were increased in IL-10/IRF-1(-/-) compared with WT and IL-10(-/-) colonic CD11b(+) lamina propria mononuclear cells. In conclusion, these experiments characterize IRF-ISRE interactions on the Il23a promoter, which have in vivo relevance as a homeostatic checkpoint in chronic intestinal inflammation.

Characterization of an interferon-stimulated response element (ISRE) in the Il23a promoter.

Regulation of innate inflammatory responses against the enteric microbiota is essential for the maintenance of intestinal homeostasis. Key participants in innate defenses are macrophages. In these studies, the basic leucine zipper protein, NFIL3, is identified as a regulatory transcription factor in macrophages, controlling IL-12 p40 production induced by bacterial products and the enteric microbiota. Exposure to commensal bacteria and bacterial products induced NFIL3 in cultured macrophages and in vivo. The Il12b promoter has a putative DNA-binding element for NFIL3. Basal and LPS-activated NFIL3 binding to this site was confirmed by chromatin immunoprecipitation. LPS-induced Il12b promoter activity was inhibited by NFIL3 expression and augmented by NFIL3-short hairpin RNA in an Il12b-bacterial artificial chromosome-GFP reporter macrophage line. Il12b inhibition by NFIL3 does not require IL-10 expression, but a C-terminal minimal repression domain is necessary. Furthermore, colonic CD11b(+) lamina propria mononuclear cells from Nfil3(-/-) mice spontaneously expressed Il12b mRNA. Importantly, lower expression of NFIL3 was observed in CD14(+) lamina propria mononuclear cells from Crohn's disease and ulcerative colitis patients compared with control subjects. Likewise, no induction of Nfil3 was observed in colons of colitis-prone Il10(-/-) mice transitioned from germ-free to a conventional microbiota. In conclusion, these experiments characterize NFIL3 as an Il12b transcriptional inhibitor. Interactions of macrophages with the enteric microbiota induce NFIL3 to limit their inflammatory capacity. Furthermore, altered intestinal NFIL3 expression may have implications for the pathogenesis of experimental and human inflammatory bowel diseases.

NFIL3 is a regulator of IL-12 p40 in macrophages and mucosal immunity.

Cigarette smoking is a significant environmental factor in the human inflammatory bowel diseases, remarkably, conferring protection in ulcerative colitis. We previously demonstrated that a prominent component of cigarette smoke, CO, suppresses Th17-mediated experimental colitis in IL-10(-/-) mice through a heme oxygenase (HO)-1-dependent pathway. In this study, homeostatic and therapeutic effects of CO and HO-1 were determined in chronic colonic inflammation in TCR-α-deficient ((-/-)) mice, in which colitis is mediated by Th2 cytokines, similar to the cytokine milieu described in human ulcerative colitis. TCRα(-/-) mice exposed to CO or treated with the pharmacologic HO-1 inducer cobalt protoporphyrin demonstrated amelioration of active colitis. CO and cobalt protoporphyrin suppressed colonic IL-1β, TNF, and IL-4 production, whereas IL-10 protein secretion was increased. CO induced IL-10 expression in macrophages and in vivo through an HO-1-dependent pathway. Bacterial products regulate HO-1 expression in macrophages through MyD88- and IL-10-dependent pathways. CO exposure and pharmacologic HO-1 induction in vivo resulted in increased expression of HO-1 and IL-10 in CD11b(+) lamina propria mononuclear cells. Moreover, induction of the IL-10 family member IL-22 was demonstrated in CD11b(-) lamina propria mononuclear cells. In conclusion, CO and HO-1 induction ameliorated active colitis in TCRα(-/-) mice, and therapeutic effects correlated with induction of IL-10. This study provides further evidence that HO-1 mediates an important homeostatic pathway with pleiotropic anti-inflammatory effects in different experimental models of colitis and that targeting HO-1, therefore, is a potential therapeutic strategy in human inflammatory bowel diseases.

An anti-inflammatory role for carbon monoxide and heme oxygenase-1 in chronic Th2-mediated murine colitis.

To prevent excessive inflammatory responses to commensal microbes, intestinal macrophages, unlike their systemic counterparts, do not produce inflammatory cytokines in response to enteric bacteria. Consequently, loss of macrophage tolerance to the enteric microbiota plays a central role in the pathogenesis of inflammatory bowel diseases. Therefore, we examined whether the hyporesponsive phenotype of intestinal macrophages is programmed by prior exposure to the microbiota. IL-10, but not in vivo exposure to the microbiota, programs intestinal macrophage tolerance, because wild-type (WT) colonic macrophages from germ-free and specific pathogen-free (SPF)-derived mice produce IL-10, but not IL-12 p40, when activated with enteric bacteria. Basal and activated IL-10 expression is mediated through a MyD88-dependent pathway. Conversely, colonic macrophages from germ-free and SPF-derived colitis-prone Il10(-/-) mice demonstrated robust production of IL-12 p40. Next, mechanisms through which IL-10 inhibits Il12b expression were investigated. Although Il12b mRNA was transiently induced in LPS-activated WT bone marrow-derived macrophages (BMDMs), expression persisted in Il10(-/-) BMDMs. There were no differences in nucleosome remodeling, mRNA stability, NF-κB activation, or MAPK signaling to explain prolonged transcription of Il12b in Il10(-/-) BMDMs. However, acetylated histone H4 transiently associated with the Il12b promoter in WT BMDMs, whereas association of these factors was prolonged in Il10(-/-) BMDMs. Experiments using histone deacetylase (HDAC) inhibitors and HDAC3 short hairpin RNA indicate that HDAC3 is involved in histone deacetylation of the Il12b promoter by IL-10. These results suggest that histone deacetylation on the Il12b promoter by HDAC3 mediates homeostatic effects of IL-10 in macrophages.

IL-10 regulates Il12b expression via histone deacetylation: implications for intestinal macrophage homeostasis.

&#x80CC;&#x666F; &amp; &#x76EE;&#x7684;&#xFF1A; &#x8840;&#x7EA2;&#x7D20;&#x52A0;&#x6C27;&#x9176;-1 (&#x4F55;-1&#xFF09; &#x548C;&#x5176;&#x4EE3;&#x8C22;&#x526F;&#x4EA7;&#x7269;&#xFF0C;&#x4E00;&#x6C27;&#x5316;&#x78B3; (CO)&#x3001; &#x4FDD;&#x62A4;&#x5BF9;&#x5B9E;&#x9A8C;&#x6027;&#x7ED3;&#x80A0;&#x708E;&#x3001; &#x80A0;&#x9053;&#x708E;&#x75C7;&#xFF0C;&#x4F46;&#x6709;&#x5173;&#x5176;&#x80A0;&#x9053;&#x514D;&#x75AB;&#x673A;&#x5236;&#x6240;&#x77E5;&#x751A;&#x5C11;&#x3002;&#x6211;&#x4EEC;&#x8C03;&#x67E5;&#x6709;&#x9650;&#x516C;&#x53F8;&#x4E4B;&#x95F4;&#x7684;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x4F55;-1&#xFF0C;&#x5E76;&#x5728;&#x5C0F;&#x9F20;&#x548C;&#x6591;&#x9A6C;&#x9C7C;&#x7684;&#x80A0;&#x9053;&#x83CC;&#x7FA4;&#x3002;&#x65B9;&#x6CD5;&#xFF1A; &#x65E0;&#x83CC;&#x3001; &#x91CE;&#x751F;&#x578B;&#x548C;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20; (Il)10(-/-) &#x5C0F;&#x9F20;&#x3001; &#x65E0;&#x83CC;&#x7684;&#x6591;&#x9A6C;&#x9C7C;&#x80DA;&#x80CE;&#x5904;&#x4E8E;&#x6B96;&#x6C11;&#x4E0E;&#x65E0;&#x75C5;&#x539F; (SPF)&#x3002;&#x65E0;&#x83CC;&#x6216; SPF &#x63D0;&#x51FA;&#x7684;&#x91CE;&#x751F;&#x578B;&#x548C; Il10(-/-) &#x5C0F;&#x9F20;&#x90FD;&#x6709;&#x5411;&#x4E0A;&#x8C03;&#x8282;&#x4F55;-1&#x3001; CO-releasing &#x5206;&#x5B50; alfama CO-releasing &#x5206;&#x5B50; 186 &#x6216;&#x751F;&#x7406;&#x76D0;&#x6C34; (&#x63A7;&#x5236;) &#x7684;&#x94B4;&#x535F; (&#x751F;&#x4EA7;&#x8005;) &#x8179;&#x8154;&#x6CE8;&#x5C04;&#x3002;&#x7ED3;&#x80A0;&#x708E;&#x662F;&#x91CE;&#x751F;&#x578B;&#x5C0F;&#x9F20;&#x5B89;&#x7F6E;&#x5728; SPF &#x6761;&#x4EF6;&#x7531;&#x9F20;&#x4F24;&#x5BD2;&#x6C99;&#x95E8;&#x6C0F;&#x83CC;&#x611F;&#x67D3;&#x5F15;&#x8D77;&#x7684;&#x3002;&#x7ED3;&#x679C;&#xFF1A; &#x5728;&#x65E0;&#x83CC;&#x3001; &#x91CE;&#x751F;&#x578B;&#x5C0F;&#x9F20;&#x7684;&#x5192;&#x53F7;&#xFF0C;SPF &#x83CC;&#x7FA4;&#x8BF1;&#x5BFC;&#x4F55; 1 &#x901A;&#x8FC7;&#x6FC0;&#x6D3B; NF E2 &#x76F8;&#x5173;&#x56E0;&#x5B50; 2-&#x751F;&#x4EA7;&#x3001; IL-10-&#x4E0E; Toll &#x6837;&#x53D7;&#x4F53;&#x4F9D;&#x8D56;&#x7684;&#x9014;&#x5F84; &#xFF1B;&#x5728;&#x6591;&#x9A6C;&#x9C7C;&#x4E2D;&#x63D0;&#x51FA;&#x4E86;&#x7C7B;&#x4F3C;&#x7684;&#x610F;&#x89C1;&#x3002;SPF &#x83CC;&#x7FA4;&#x4E0D;&#x786E;&#x5B9E;&#x5728;&#x5192;&#x53F7;&#x7684;&#x65E0;&#x83CC; Il10(-/-) &#x5C0F;&#x9F20;&#x4FC3;&#x4F7F;&#x4F55; 1&#x3002;&#x5F53;&#x5C40;&#x4ECE; SPF &#x6761;&#x4EF6;&#x65E0;&#x83CC; Il10(-/-) &#x5C0F;&#x9F20;&#x524D;&#x8FC7;&#x6E21;&#x5230;&#x751F;&#x4EA7;&#x8005;&#x51CF;&#x5C11;&#x7ED3;&#x80A0;&#x708E;&#x7684;&#x53D1;&#x5C55;&#x3002;Il10(-/-) &#x5C0F;&#x9F20; CO &#x548C;&#x751F;&#x4EA7;&#x8005;&#x51CF;&#x5C11;&#x80A0;&#x9053;&#x7EC6;&#x83CC;&#x57FA;&#x56E0;&#x7EC4; DNA &#x4E2D;&#x80A0;&#x7CFB;&#x819C;&#x6DCB;&#x5DF4;&#x7ED3;&#x7684;&#x6C34;&#x5E73;&#x3002;S &#x9F20;&#x4F24;&#x5BD2;&#x5F15;&#x8D77;&#x5C0F;&#x80A0;&#x7ED3;&#x80A0;&#x708E;&#x5C0F;&#x9F20;&#xFF0C;&#x751F;&#x4EA7;&#x8005;&#x51CF;&#x5C11;&#x6062;&#x590D;&#x4ECE;&#x56FA;&#x6709;&#x3001; &#x80A0;&#x7CFB;&#x819C;&#x6DCB;&#x5DF4;&#x7ED3;&#x3001; &#x813E;&#x548C;&#x809D;&#x7684;&#x6D3B; S &#x4F24;&#x5BD2;&#x7684;&#x4EBA;&#x6570;&#x3002;&#x2477; &#x4F55;-1 &#x5728;&#x5C0F;&#x9F20;&#x5DE8;&#x566C;&#x7EC6;&#x80DE;&#x53D7;&#x635F;&#x5BF9;&#x5927;&#x80A0;&#x6746;&#x83CC;&#x3001; E &#x7CAA;&#x548C; S &#x9F20;&#x4F24;&#x5BD2;&#xFF0C;&#x5176;&#x6740;&#x83CC;&#x6D3B;&#x6027;&#x800C;&#x66B4;&#x9732;&#x4E8E; CO &#x6216;&#x8868;&#x8FBE;&#x7684;&#x4F55; 1 &#x589E;&#x52A0;&#x5176;&#x6740;&#x83CC;&#x6D3B;&#x6027;&#x3002;&#x4F55;-1 &#x8BF1;&#x5BFC;&#x548C; CO &#x589E;&#x52A0;&#x541E;&#x566C;&#x7684;&#x4F53;&#x5185;&#x9178;&#x5316;&#x3002;&#x7ED3;&#x8BBA;&#xFF1A; &#x7ED3;&#x80A0;&#x4F55; 1 &#x53EF;&#x9632;&#x6B62;&#x5C0F;&#x9F20;&#x7ED3;&#x80A0;&#x708E;&#x75C7;&#x3002;&#x4F55;-1 &#x5F15;&#x8D77;&#x7684;&#x80A0;&#x9053;&#x83CC;&#x7FA4;&#x548C;&#x4ECB;&#x5BFC;&#x5176;&#x6052;&#x4E45;&#x7684;&#x529F;&#x80FD;&#xFF0C;&#x90E8;&#x5206;&#x5730;&#x901A;&#x8FC7;&#x4FC3;&#x8FDB;&#x5DE8;&#x566C;&#x7EC6;&#x80DE;&#x7684;&#x6740;&#x83CC;&#x6D3B;&#x6027;&#x3002;

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BACKGROUND & AIMS: Heme oxygenase-1 (HO-1) and its metabolic by-product, carbon monoxide (CO), protect against intestinal inflammation in experimental models of colitis, but little is known about their intestinal immune mechanisms. We investigated the interactions among CO, HO-1, and the enteric microbiota in mice and zebrafish. METHODS: Germ-free, wild-type, and interleukin (Il)10(-/-) mice and germ-free zebrafish embryos were colonized with pathogen-free (SPF). Germ-free or SPF-raised wild-type and Il10(-/-) mice were given intraperitoneal injections of cobalt protoporphyrin (CoPP), which up-regulates HO-1, the CO-releasing molecule alfama CO-releasing molecule 186, or saline (control). Colitis was induced in wild-type mice housed in SPF conditions by infection with Salmonella typhimurium. RESULTS: In colons of germ-free, wild-type mice, SPF microbiota induced production of HO-1 via activation of NF-E2-related factor 2-, IL-10-, and Toll-like receptor-dependent pathways; similar observations were made in zebrafish. SPF microbiota did not induce HO-1 in colons of germ-free Il10(-/-) mice. Administration of CoPP to Il10(-/-) mice before transition from germ-free to SPF conditions reduced their development of colitis. In Il10(-/-) mice, CO and CoPP reduced levels of enteric bacterial genomic DNA in mesenteric lymph nodes. In mice with S typhimurium-induced enterocolitis, CoPP reduced the numbers of live S typhimurium recovered from the lamina propria, mesenteric lymph nodes, spleen, and liver. Knockdown of HO-1 in mouse macrophages impaired their bactericidal activity against E coli, E faecalis, and S typhimurium, whereas exposure to CO or overexpression of HO-1 increased their bactericidal activity. HO-1 induction and CO increased acidification of phagolysosomes. CONCLUSIONS: Colonic HO-1 prevents colonic inflammation in mice. HO-1 is induced by the enteric microbiota and its homeostatic function is mediated, in part, by promoting bactericidal activities of macrophages.

Carbon Monoxide and Heme Oxygenase-1 Prevent Intestinal Inflammation in Mice by Promoting Bacterial Clearance.

BACKGROUND &amp; AIMS : H&egrave;me oxyg&eacute;nase-1 (HO-1) et son d&eacute;riv&eacute; m&eacute;tabolique, le monoxyde de carbone (CO), prot&egrave;gent contre l&#39;inflammation intestinale dans des mod&egrave;les exp&eacute;rimentaux de la colite, mais on conna&icirc;t leurs m&eacute;canismes immunitaires intestinales. Nous avons &eacute;tudi&eacute; les interactions entre les CO, HO-1 et la microflore ent&eacute;rique chez la souris et le poisson-z&egrave;bre. M&eacute;thodes : Germ-free, sauvage et interleukin (Il)10(-/-) souris et sans germes zebrafish embryons ont &eacute;t&eacute; colonis&eacute;s par exempts de micro-organismes pathog&egrave;nes (SPF). Germ-free ou SPF-d&eacute;clench&eacute; sauvage et Il10(-/-) souris ont re&ccedil;u des injections intrap&eacute;riton&eacute;ales de la protoporphyrine de cobalt (CoPP), qui r&eacute;glemente d&#39;up HO-1, la mol&eacute;cule alfama diffusant mol&eacute;cule 186 CO-releasing ou une solution saline (contr&ocirc;le). Colite a &eacute;t&eacute; induite chez les souris de type sauvage log&eacute;s dans des conditions de SPF par une infection &agrave; Salmonella typhimurium. R&Eacute;SULTATS : En colones de souris ax&eacute;niques, sauvage, SPF microbiote induite par production d&#39;HO-1 via l&#39;activation du facteur NF-E2-connexes 2-, IL - 10 - et Toll-like receptor-d&eacute;pendante voies ; des observations similaires ont &eacute;t&eacute; faites chez le poisson z&egrave;bre. Microbiota SPF n&#39;induit pas de HO-1 dans les colones de germ-free Il10(-/-) souris. Administration de CoPP Il10(-/-) souris avant la transition de germ-free aux conditions SPF r&eacute;duit leur d&eacute;veloppement de colite. Chez les souris Il10(-/-), CO et CoPP r&eacute;duit les niveaux de l&#39;ADN g&eacute;nomique bact&eacute;rienne ent&eacute;rique dans les ganglions m&eacute;sent&eacute;riques. Chez la souris avec l&#39;ent&eacute;rocolite induite par typhimurium S, CoPP a r&eacute;duit le nombre de vivant S typhimurium, extraite de la lamina propria, ganglions m&eacute;sent&eacute;riques, rate et le foie. Pr&eacute;cipitation d&#39;HO-1 dans les macrophages de souris atteinte leur activit&eacute; bact&eacute;ricide contre E. coli, E faecalis et typhimurium S, alors que l&#39;exposition au CO ou la surexpression de HO-1 a augment&eacute; leur activit&eacute; bact&eacute;ricide. HO-1 induction et CO ont augment&eacute; l&#39;acidification des phagolysosomes. CONCLUSIONS : Colique HO-1 emp&ecirc;che l&#39;inflammation colique chez les souris. HO-1 est induite par la microflore ent&eacute;rique et sa fonction hom&eacute;ostatique est v&eacute;hicul&eacute;e, en partie, par la promotion d&#39;activit&eacute;s bact&eacute;ricides des macrophages.

Le monoxyde de carbone et l&#39;h&egrave;me oxyg&eacute;nase-1 pr&eacute;viennent l&#39;Inflammation intestinale chez les souris en promouvant la clairance bact&eacute;rienne.

Hintergrund &amp; Ziele: H&auml;m-Oxygenase-1 (HO-1) und seine metabolischen Nebenprodukt, Kohlenmonoxid (CO), Schutz gegen Darmentz&uuml;ndungen in experimentellen Modellen der Kolitis, sondern &uuml;ber ihre Darm-immun-Mechanismen ist wenig bekannt. Wir untersuchten die Interaktionen zwischen CO, HO-1 und der enterischen Microbiota in M&auml;usen und Zebrafisch. Methoden: Keimfreies, Wildtyp und Interleukin (Il)10(-/-) M&auml;use und keimfrei Zebrafisch Embryonen mit Pathogen-freies (SPF) kolonisiert wurden. SPF-erhoben oder keimfreies Wildtyp und Il10(-/-) M&auml;use erhielten intraperitoneale Injektion von Kobalt Porphyrine (CoPP), die bis-HO-1, das CO-releasing Molek&uuml;l Alfama CO-releasing Molek&uuml;l 186 oder Kochsalzl&ouml;sung (Kontrolle regelt). Kolitis wurde im Wildtyp-M&auml;usen, die durch eine Infektion mit Salmonella Typhimurium in SPF Bedingungen untergebracht ausgel&ouml;st. Ergebnisse: In Doppelpunkte keimfrei, Wildtyp M&auml;usen, SPF Microbiota induzierte Produktion von HO-1 durch die Aktivierung des NF-E2-bezogenen Faktor 2 - IL - 10- und Toll-Like Rezeptor-abh&auml;ngige Wege; &auml;hnliche Beobachtungen erfolgten Zebrab&auml;rbling. SPF Microbiota nicht HO-1 in Doppelpunkte keimfreies Il10(-/-) M&auml;use ausl&ouml;sen. Verwaltung von CoPP, Il10(-/-) M&auml;use vor &Uuml;bergang von keimfreies SPF Bedingungen reduziert ihre Entwicklung der Kolitis. Bei Il10(-/-) M&auml;usen reduziert CO und CoPP Ebenen der enterischen bakterielle genomische DNA in mesenterischen Lymphknoten. Bei M&auml;usen mit S Typhimurium-induzierte Enterokolitis verringerte CoPP die Zahl von Leben S Typhimurium erholte sich von der Lamina Propria, mesenterischen Lymphknoten, Milz und Leber. Niederschlag &uuml;ber HO-1 in Makrophagen der Maus beeintr&auml;chtigt ihre bakterizide Aktivit&auml;t gegen e. coli, E Faecalis und S Typhimurium, w&auml;hrend die Gef&auml;hrdung durch CO oder eine &Uuml;berexpression von HO-1 ihre bakterizide Aktivit&auml;t erh&ouml;ht. HO-1-Induktion und CO erh&ouml;ht die S&auml;uerung von Phagolysosomes. Schlussfolgerungen: Kolon HO-1 verhindert Kolon Entz&uuml;ndung in den M&auml;usen. HO-1 wird induziert durch den Darm Microbiota und seine hom&ouml;ostatische Funktion ist teilweise durch die bakterizide Aktivit&auml;ten der Makrophagen vermittelt.

Kohlenmonoxid und H&auml;m-Oxygenase-1 verhindern Darmentz&uuml;ndungen bei M&auml;usen durch die F&ouml;rderung von bakteriellen Clearance.

SFONDO mira &amp;: Eme ossigenasi-1 (HO-1) e i suoi sottoprodotti metabolici, monossido di carbonio (CO), proteggere contro l&#39;infiammazione intestinale in modelli sperimentali di colite, ma poco si sa sui loro meccanismi di sistema immunitario intestinale. Abbiamo studiato le interazioni tra CO, HO-1 e il microbiota enterico nei topi e zebrafish. Metodi: Germ-free, wild-type e interleuchina (Il)10(-/-) e topi germ-free zebrafish embrioni sono stati colonizzati con privo di agenti patogeni (SPF). SPF-generato o germ-free wild-type e Il10(-/-) topi erano dato iniezioni intraperitoneali di protoporfirina di cobalto (CoPP), che in su-regola HO-1, la molecola alfama CO-releasing molecola 186 CO-releasing o soluzione salina (controllo). La colite &egrave; stata indotta in topi wild-type, alloggiati in condizioni SPF da infezione con Salmonella typhimurium. RISULTATI: In due punti dei topi germ-free, wild-type, SPF microbiota indotta da produzione di HO-1 tramite attivazione del fattore NF-E2-correlati 2-, IL - 10 - e percorsi dipendente dal recettore Toll-like; osservazioni simili sono state fatte nello zebrafish. Microbiota SPF non ha indotto HO-1 in due punti dei topi Il10(-/-) germ-free. Amministrazione di CoPP a Il10(-/-) topi prima transizione da germ-free a condizioni SPF ridotto lo sviluppo di colite. Nei topi Il10(-/-), CO e CoPP ridotti livelli di enterico DNA genomic batterico nei linfonodi mesenterici. Nei topi con enterocolite indotta da typhimurium S, CoPP ridotto i numeri della diretta S typhimurium recuperato dalla lamina propria, linfonodi mesenterici, milza e fegato. Atterramento di HO-1 nei macrofagi di topo ha alterato la loro attivit&agrave; battericida contro E. coli, E faecalis e S typhimurium, considerando che l&#39;esposizione al CO o sovraespressione di HO-1 aumentato la loro attivit&agrave; battericida. HO-1 induzione e CO aumentata acidificazione del phagolysosomes. CONCLUSIONI: Colica HO-1 previene l&#39;infiammazione del colon nei topi. HO-1 &egrave; indotta dal microbiota enterico e la sua funzione omeostatica &egrave; mediato, in parte, promuovendo attivit&agrave; battericida dei macrofagi.

Monossido di carbonio ed eme ossigenasi-1 prevenire infiammazioni intestinali nei topi promuovendo la Clearance batterica.

&#x80CC;&#x666F; &amp; &#x76EE;&#x7684;: &#x30D8;&#x30E0;&#x9178;&#x7D20;&#x6DFB;&#x52A0;&#x9175;&#x7D20;-1 &#xFF08;HO-1) &#x3068;&#x305D;&#x306E;&#x4EE3;&#x8B1D;&#x526F;&#x7523;&#x7269;&#x3001;&#x4E00;&#x9178;&#x5316;&#x70AD;&#x7D20; (CO)&#x3001;&#x5927;&#x8178;&#x708E;&#x306E;&#x5B9F;&#x9A13;&#x30E2;&#x30C7;&#x30EB;&#x3067;&#x306E;&#x8178;&#x7BA1;&#x708E;&#x75C7;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x4FDD;&#x8B77;&#x304C;&#x3001;&#x305D;&#x306E;&#x8178;&#x306E;&#x514D;&#x75AB;&#x6A5F;&#x69CB;&#x306B;&#x3064;&#x3044;&#x3066;&#x306F;&#x307B;&#x3068;&#x3093;&#x3069;&#x77E5;&#x3089;&#x308C;&#x3066;&#x3044;&#x307E;&#x305B;&#x3093;&#x3002;&#x6211;&#x3005; &#x306F; CO &#x9593;&#x306E;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x3092;&#x8ABF;&#x3079;&#x305F; HO 1 &#x3068;&#x30DE;&#x30A6;&#x30B9;&#x304A;&#x3088;&#x3073;&#x30BC;&#x30D6;&#x30E9;&#x30D5;&#x30A3;&#x30C3;&#x30B7;&#x30E5;&#x306B;&#x304A;&#x3051;&#x308B;&#x8178;&#x5185;&#x7D30;&#x83CC;&#x53E2;&#x3002;&#x65B9;&#x6CD5;: &#x751F;&#x6B96;&#x7121;&#x6599;, &#x91CE;&#x751F;&#x578B;&#x3068;&#x30A4;&#x30F3;&#x30BF;&#x30FC;&#x30ED;&#x30A4;&#x30AD;&#x30F3; &#xFF08;Il)10(-/-) &#x30DE;&#x30A6;&#x30B9;&#x3001;&#x7121;&#x83CC;&#x30BC;&#x30D6;&#x30E9;&#x30D5;&#x30A3;&#x30C3;&#x30B7;&#x30E5;&#x80DA;&#x3092;&#x7121;&#x6599;&#x306E;&#x75C5;&#x539F;&#x4F53;&#x3092; &#xFF08;SPF&#xFF09; &#x690D;&#x6C11;&#x5730;&#x5316;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x7121;&#x83CC;&#x307E;&#x305F;&#x306F; SPF &#x304C;&#x767A;&#x751F;&#x3057;&#x305F;&#x91CE;&#x751F;&#x578B;&#x3068; Il10(-/-) &#x30DE;&#x30A6;&#x30B9;&#x8179;&#x8154;&#x5185;&#x6CE8;&#x5C04; HO 1&#x3001;CO-releasing &#x30A2;&#x30EB;&#x30D5;&#x30A1;&#x30DE;&#x5206;&#x5B50;&#x3093; 186&#x3001;&#x307E;&#x305F;&#x306F;&#x751F;&#x7406;&#x98DF;&#x5869;&#x6C34; (&#x30B3;&#x30F3;&#x30C8;&#x30ED;&#x30FC;&#x30EB;) &#x3092;&#x8ABF;&#x7BC0;&#x3059;&#x308B;&#x30B3;&#x30D0;&#x30EB;&#x30C8; &#x30D7;&#x30ED;&#x30C8;&#x30DD;&#x30EB;&#x30D5;&#x30A3;&#x30EA;&#x30F3; (CoPP) &#x304C;&#x4E0E;&#x3048;&#x3089;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x5927;&#x8178;&#x708E;&#x306F; SPF &#x306E;&#x6761;&#x4EF6;&#x3067;&#x306E;&#x30B5;&#x30EB;&#x30E2;&#x30CD;&#x30E9;&#x611F;&#x67D3;&#x306B;&#x3088;&#x308B;&#x5EFA;&#x7269;&#x91CE;&#x751F;&#x578B;&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x8A98;&#x5C0E;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x7D50;&#x679C;: &#x7121;&#x83CC;&#x3001;&#x91CE;&#x751F;&#x578B;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x30B3;&#x30ED;&#x30F3;&#x8A98;&#x8D77; SPF &#x5FAE;&#x751F;&#x7269;&#x53E2; HO 1 &#x306E;&#x751F;&#x7523; NF E2 &#x95A2;&#x9023;&#x56E0;&#x5B50; 2 - &#x306E;&#x6D3B;&#x6027;&#x5316;&#x3092;&#x901A;&#x3058;&#x3066;&#x3001;IL - 10 - &#x3068; Toll &#x69D8;&#x53D7;&#x5BB9;&#x4F53;&#x4F9D;&#x5B58;&#x6027;&#x7D4C;&#x8DEF;&#x3002;&#x4F3C;&#x305F;&#x3088;&#x3046;&#x306A;&#x89B3;&#x6E2C;&#x306F;&#x3001;&#x30BC;&#x30D6;&#x30E9;&#x30D5;&#x30A3;&#x30C3;&#x30B7;&#x30E5;&#x3067;&#x884C;&#x308F;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;SPF &#x5FAE;&#x751F;&#x7269;&#x53E2; HO 1 Il10(-/-) &#x30DE;&#x30A6;&#x30B9;&#x306E;&#x30B3;&#x30ED;&#x30F3;&#x3067;&#x306F;&#x8A98;&#x5C0E;&#x3055;&#x308C;&#x306A;&#x304B;&#x3063;&#x305F;&#x3002;&#x7BA1;&#x7406;&#x306B;&#x79FB;&#x884C;&#x3059;&#x308B;&#x524D;&#x306B; Il10(-/-) &#x30DE;&#x30A6;&#x30B9; CoPP &#x7121;&#x83CC; SPF &#x306E;&#x6761;&#x4EF6;&#x304B;&#x3089;&#x306E;&#x5927;&#x8178;&#x708E;&#x306E;&#x958B;&#x767A;&#x306B;&#x524A;&#x6E1B;&#x3002;Il10(-/-) &#x30DE;&#x30A6;&#x30B9;&#x3067; CO &#x3068; CoPP &#x4E0A;&#x8178;&#x9593;&#x819C;&#x30EA;&#x30F3;&#x30D1;&#x7BC0;&#x306B;&#x304A;&#x3051;&#x308B;&#x8178;&#x5185;&#x7D30;&#x83CC; DNA &#x306E;&#x30EC;&#x30D9;&#x30EB;&#x3092;&#x6E1B;&#x3089;&#x3057;&#x305F;&#x3002;S &#x30B5;&#x30EB;&#x30E2;&#x30CD;&#x30E9;&#x8178;&#x708E;&#x306E;&#x30DE;&#x30A6;&#x30B9;&#x3067; CoPP &#x7C98;&#x819C;&#x56FA;&#x6709;&#x5C64;, &#x8178;&#x9593;&#x819C;&#x30EA;&#x30F3;&#x30D1;&#x7BC0;, &#x813E;&#x81D3;&#x304A;&#x3088;&#x3073;&#x809D;&#x81D3;&#x304B;&#x3089;&#x56DE;&#x5FA9;&#x3057;&#x305F;&#x30E9;&#x30A4;&#x30D6;&#x306E; S &#x83CC;&#x6570;&#x6E1B;&#x5C11;&#x3002;&#x305D;&#x306E;&#x6BBA;&#x83CC;&#x4F5C;&#x7528;&#x306E; CO &#x3084; HO 1 &#x306E;&#x904E;&#x5270;&#x767A;&#x73FE;&#x3078;&#x306E;&#x66B4;&#x9732;&#x306E;&#x5897;&#x52A0;&#x306B;&#x5BFE;&#x3057;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x30DE;&#x30AF;&#x30ED;&#x30D5;&#x30A1;&#x30FC;&#x30B8;&#x3067;&#x306E; ho-1 &#x306E;&#x30CE;&#x30C3;&#x30AF;&#x30C0;&#x30A6;&#x30F3;&#x305D;&#x306E;&#x5927;&#x8178;&#x83CC;&#x3001;E &#x8178;&#x3001;S &#x578B;&#x30CD;&#x30BA;&#x30DF;&#x30C1;&#x30D5;&#x30B9;&#x83CC;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x6BBA;&#x83CC;&#x4F5C;&#x7528;&#x969C;&#x5BB3;&#x3002;HO 1 &#x8A98;&#x5C0E;&#x3068; CO &#x30D5;&#x30A1;&#x30B4;&#x30EA;&#x30BD;&#x30BD;&#x30FC;&#x30E0;&#x306E;&#x9178;&#x6027;&#x5316;&#x3092;&#x5897;&#x52A0;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x7D50;&#x8AD6;: &#x5927;&#x8178; HO 1 &#x30DE;&#x30A6;&#x30B9;&#x306E;&#x5927;&#x8178;&#x306E;&#x708E;&#x75C7;&#x3092;&#x9632;&#x304E;&#x307E;&#x3059;&#x3002;HO 1 &#x8178;&#x5185;&#x7D30;&#x83CC;&#x53E2;&#x306B;&#x3088;&#x3063;&#x3066;&#x8A98;&#x5C0E;&#x3055;&#x308C;&#x3001;&#x305D;&#x306E;&#x6052;&#x5E38;&#x6027;&#x6A5F;&#x80FD;&#x3001;&#x4E00;&#x90E8;&#x3067;&#x306F;&#x3001;&#x30DE;&#x30AF;&#x30ED;&#x30D5;&#x30A1;&#x30FC;&#x30B8;&#x306E;&#x6BBA;&#x83CC;&#x4F5C;&#x7528;&#x3092;&#x4FC3;&#x9032;&#x3059;&#x308B;&#x3053;&#x3068;&#x306B;&#x3088;&#x3063;&#x3066;&#x5A92;&#x4ECB;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;

&#x4E00;&#x9178;&#x5316;&#x70AD;&#x7D20;&#x3068;&#x30D8;&#x30E0;&#x9178;&#x7D20;&#x6DFB;&#x52A0;&#x9175;&#x7D20; 1 &#x7D30;&#x83CC;&#x30AF;&#x30EA;&#x30A2;&#x30E9;&#x30F3;&#x30B9;&#x306E;&#x4FC3;&#x9032;&#x306B;&#x3088;&#x3063;&#x3066;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x8178;&#x7BA1;&#x306E;&#x708E;&#x75C7;&#x3092;&#x9632;&#x3050;&#x3002;

&#xBC30;&#xACBD; &amp; &#xBAA9;&#xD45C;: &#xC2E4;&#xD5D8; &#xBAA8;&#xB378;&#xC758; &#xB300; &#xC7A5; &#xC5FC;, &#xC7A5; &#xC5FC;&#xC99D; &#xC73C;&#xB85C;&#xBD80;&#xD130; &#xBCF4;&#xD638; &#xD558;&#xB294; Heme oxygenase-1 (1 &#xD638;)&#xC640; &#xB300;&#xC0AC; &#xBD80;&#xC0B0;&#xBB3C;, &#xC77C;&#xC0B0;&#xD654; &#xD0C4;&#xC18C; (CO), &#xD558;&#xC9C0;&#xB9CC; &#xC57D;&#xAC04;&#xC758; &#xC7A5;&#xB0B4; &#xBA74;&#xC5ED; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC5D0; &#xB300; &#xD55C; &#xC54C;&#xB824;&#xC838; &#xC788;&#xB2E4;. &#xC6B0;&#xB9AC; &#xACF5;&#xB3D9; &#xAC04;&#xC758; &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC744; &#xC870;&#xC0AC; &#xD638;-1, &#xADF8;&#xB9AC;&#xACE0; &#xC950;&#xC640; zebrafish &#xC7A5;&#xC758; microbiota. &#xBC29;&#xBC95;: &#xC138;&#xADE0; &#xC5C6;&#xB294; &#xC57C;&#xC0DD; &#xD615; &#xBC0F; &#xC778;&#xD130; &#xB8E8; &#xD0A8; (Il)10(-/-) &#xB9C8;&#xC6B0;&#xC2A4; &#xBC0F; &#xC138;&#xADE0; &#xC5C6;&#xB294; zebrafish &#xD0DC;&#xC544; &#xBCD1;&#xC6D0; &#xCCB4; &#xBB34;&#xB8CC; (spf)&#xB97C; &#xC2DD;&#xBBFC;&#xC9C0; &#xD654; &#xD588;&#xB2E4;. &#xC138;&#xADE0; &#xB610;&#xB294; SPF &#xBC1C;&#xC0DD; &#xC57C;&#xC0DD;-&#xD0C0;&#xC785; &#xBC0F; Il10(-/-) &#xB9C8;&#xC6B0;&#xC2A4; &#xCD5C;&#xB300; &#xC870;&#xC815; &#xD638;-1, CO-releasing &#xBD84;&#xC790; &#xC54C;&#xD30C;&#xB9C8; &#xAE30;&#xB85D;&#xC740; &#xBD84;&#xC790; 186, &#xB610;&#xB294; &#xC2DD; &#xC5FC; &#xC218; (&#xC81C;&#xC5B4;) &#xCF54;&#xBC1C;&#xD2B8; protoporphyrin (CoPP)&#xC758; intraperitoneal &#xC8FC;&#xC0AC;&#xB97C; &#xBD80;&#xC5EC; &#xD588;&#xB2E4;. &#xB300; &#xC7A5; &#xC5FC; &#xC0B4; &#xBAA8; &#xB12C; &#xB77C; &#xD2F0;&#xC640; &#xAC10;&#xC5FC;&#xC5D0; &#xC758;&#xD574; SPF &#xC870;&#xAC74;&#xC5D0;&#xC11C; &#xBCF4;&#xAD00; &#xB418;&#xC5B4; &#xC57C;&#xC0DD;-&#xD0C0;&#xC785; &#xB9C8;&#xC6B0;&#xC2A4;&#xC5D0; &#xC720;&#xB3C4; &#xB418;&#xC5C8;&#xB2E4;. &#xACB0;&#xACFC;: &#xC138;&#xADE0; &#xC5C6;&#xB294;, &#xC57C;&#xC0DD;-&#xD0C0;&#xC785; &#xB9C8;&#xC6B0;&#xC2A4;&#xC758; &#xCF5C;&#xB860;&#xC5D0; SPF microbiota &#xC720;&#xB3C4; NF E2 &#xAD00;&#xB828; &#xC694;&#xC778; 2-&#xC758; &#xD65C;&#xC131;&#xD654;&#xB97C; &#xD1B5;&#xD574; &#xD638;-1&#xC758; &#xC0DD;&#xC0B0;, IL-10-&#xBC0F; &#xC218;&#xC2E0;&#xC790;&#xC640; &#xAC19;&#xC740; &#xC218;&#xC6A9; &#xCCB4;&#xC5D0; &#xC885;&#xC18D;&#xC801;&#xC778; &#xACBD;&#xB85C;; zebrafish &#xBE44;&#xC2B7;&#xD55C; &#xAD00;&#xCE21; &#xB418;&#xC5C8;&#xB2E4;. SPF microbiota &#xC138;&#xADE0; &#xBB34;&#xB8CC; Il10(-/-) &#xC950;&#xC758; &#xCF5C;&#xB860;&#xC5D0; &#xD638; 1&#xC744; &#xC720;&#xB3C4; &#xD558;&#xC9C0; &#xC54A;&#xC558;&#xB2E4;. &#xC138;&#xADE0; &#xC5C6;&#xB294; SPF &#xC870;&#xAC74; &#xD558;&#xC5D0;&#xC11C; &#xC804;&#xD658; &#xD558;&#xAE30; &#xC804;&#xC5D0; Il10(-/-) &#xC950; Copp&#xC758; &#xAC10;&#xC18C; colitis&#xC758; &#xAC1C;&#xBC1C;. Il10(-/-) &#xB9C8;&#xC6B0;&#xC2A4;, CO &#xBC0F; CoPP mesenteric &#xB9BC;&#xD504;&#xC808;&#xC5D0; &#xC7A5;&#xC758; &#xC138;&#xADE0;&#xC131; &#xAC8C;&#xB188; DNA &#xB808;&#xBCA8; &#xAC10;&#xC18C;. S &#xD2F0; &#xC720;&#xB3C4; enterocolitis&#xC640; &#xC0DD;&#xC950;&#xC5D0;&#xC11C; CoPP &#xB77C;&#xC774;&#xBE0C; S &#xD2F0; lamina propria, mesenteric &#xB9BC;&#xD504;&#xC808;, &#xBE44;&#xC7A5; &#xBC0F; &#xAC04;&#xC5D0;&#xC11C; &#xBC1C;&#xACAC; &#xD55C; &#xC218;&#xAC00; &#xAC10;&#xC18C;. &#xB9C8;&#xC6B0;&#xC2A4; &#xB300; &#xC2DD; &#xC138;&#xD3EC;&#xC5D0;&#xC11C; &#xD638; 1&#xC758; &#xCD5C;&#xC800; CO &#xB610;&#xB294; &#xD638; 1&#xC758; overexpression&#xC5D0; &#xB300; &#xD55C; &#xB178;&#xCD9C;&#xC744; &#xC99D;&#xAC00; &#xADF8;&#xB4E4;&#xC758; &#xC0B4; &#xADE0; &#xD65C;&#xB3D9; &#xD558;&#xB294; &#xBC18;&#xBA74; E &#xB300;&#xC7A5;&#xADE0;, E faecalis, &#xBC0F; S &#xD2F0;&#xC5D0; &#xB300; &#xD55C; &#xC0B4; &#xADE0;&#xC758; &#xD65C;&#xB3D9; &#xC7A5;&#xC560;. &#xD638;-1 &#xC720;&#xB3C4; &#xBC0F; &#xACF5;&#xB3D9; phagolysosomes&#xC758; &#xC0B0;&#xC131;&#xD654;&#xB97C; &#xC99D;&#xAC00;. &#xACB0;&#xB860;: &#xC800; &#xC2B9; &#xD638; 1 &#xC950; &#xC800; &#xC2B9; &#xC5FC;&#xC99D;&#xC744; &#xBC29;&#xC9C0;&#xD569;&#xB2C8;&#xB2E4;. &#xD638; 1 &#xC7A5;&#xC758; microbiota&#xC5D0; &#xC758;&#xD574; &#xC720;&#xB3C4; &#xBC0F; &#xD56D;&#xC0C1;&#xC131; &#xAE30;&#xB2A5;, &#xBD80;&#xBD84;, &#xB300; &#xC2DD; &#xC138;&#xD3EC;&#xC758; &#xC0B4; &#xADE0; &#xD65C;&#xB3D9;&#xC744; &#xD64D;&#xBCF4; &#xD558; &#xC5EC; &#xC911;&#xC7AC;&#xC785;&#xB2C8;&#xB2E4;.

&#xC77C;&#xC0B0;&#xD654; &#xD0C4;&#xC18C;&#xC640; Heme Oxygenase-1 &#xC138;&#xADE0;&#xC131; &#xD074;&#xB9AC;&#xC5B4;&#xB7F0;&#xC2A4;&#xB97C; &#xD64D;&#xBCF4; &#xD558; &#xC5EC; &#xC950;&#xC758; &#xC7A5;&#xB0B4; &#xC5FC;&#xC99D; &#xBC29;&#xC9C0;.

Fondo &amp; objetivos: Heme oxigenasa-1 (HO-1) y sus subproductos metab&oacute;licos, mon&oacute;xido de carbono (CO), protegen contra la inflamaci&oacute;n intestinal en modelos experimentales de la colitis, pero poco se sabe sobre sus mecanismos inmunes intestinales. Investigamos las interacciones entre CO, HO-1 y la microbiota ent&eacute;rica en ratones y peces cebra. M&Eacute;TODOS: Libre de g&eacute;rmenes, tipo salvaje e interleuquina (Il)10(-/-) ratones y peces cebra libre de g&eacute;rmenes embriones fueron colonizados con libre de pat&oacute;genos (SPF). Libre de g&eacute;rmenes o SPF-levantado salvaje-tipo y Il10(-/-) ratones recibieron inyecciones intraperitoneales de la protoporfirina de cobalto (CoPP), que para arriba-regula HO-1, la mol&eacute;cula alfama CO-releasing mol&eacute;cula 186 CO-releasing o soluci&oacute;n salina (control). La colitis fue inducida en ratones de tipo salvaje ubicados en condiciones SPF por la infecci&oacute;n con Salmonella typhimurium. Resultados: En colones de ratones libres de g&eacute;rmenes, salvaje-tipo, SPF microbiota inducida producci&oacute;n de HO-1 mediante la activaci&oacute;n de NF-E2-related factor 2 - IL - 10 - y Toll-like receptor dependiente v&iacute;as; observaciones similares se realizaron en el pez cebra. Microbiota SPF no indujo HO-1 en colones de ratones de Il10(-/-) libre de g&eacute;rmenes. Administraci&oacute;n de CoPP Il10(-/-) ratones antes de transici&oacute;n de libre de g&eacute;rmenes a condiciones SPF redujo su desarrollo de la colitis. En los ratones Il10(-/-), CO y CoPP reducen niveles de ADN gen&oacute;mico bacterias ent&eacute;rica en ganglios linf&aacute;ticos mesent&eacute;ricos. En ratones con enterocolitis inducida por typhimurium de S, CoPP reduce el n&uacute;mero de vivo typhimurium de S que se recuper&oacute; de la l&aacute;mina propia, ganglios linf&aacute;ticos mesent&eacute;ricos, bazo y h&iacute;gado. Ca&iacute;da de HO-1 en macr&oacute;fagos de rat&oacute;n hab&iacute;a deteriorada su actividad bactericida frente a E. coli y E faecalis S typhimurium, mientras que la exposici&oacute;n a CO o sobreexpresi&oacute;n de HO-1 aument&oacute; su actividad bactericida. HO-1 inducci&oacute;n y CO mayor acidificaci&oacute;n de phagolysosomes. CONCLUSIONES: HO-1 colon previene la inflamaci&oacute;n col&oacute;nica en ratones. HO-1 se induce por la microbiota ent&eacute;rica y su funci&oacute;n homeost&aacute;tica es mediada, en parte, mediante la promoci&oacute;n de actividades bactericidas de los macr&oacute;fagos.

Mon&oacute;xido de carbono y Heme oxigenasa-1 previenen inflamaci&oacute;n Intestinal en ratones por promover la separaci&oacute;n bacteriana.

NFIL3 is a transcription factor that regulates multiple immunologic functions. In myeloid cells, NFIL3 is IL-10 inducible and has a key role as a repressor of IL-12p40 transcription. NFIL3 is a susceptibility gene for the human inflammatory bowel diseases. In this article, we describe spontaneous colitis in Nfil3(-/-) mice. Mice lacking both Nfil3 and Il10 had severe early-onset colitis, suggesting that NFIL3 and IL-10 independently regulate mucosal homeostasis. Lymphocytes were necessary for colitis, because Nfil3/Rag1 double-knockout mice were protected from disease. However, Nfil3/Rag1 double-knockout mice adoptively transferred with wild-type CD4(+) T cells developed severe colitis compared with Rag1(-/-) recipients, suggesting that colitis was linked to defects in innate immune cells. Colitis was abrogated in Nfil3/Il12b double-deficient mice, identifying Il12b dysregulation as a central pathogenic event. Finally, germ-free Nfil3(-/-) mice do not develop colonic inflammation. Thus, NFIL3 is a microbiota-dependent, IL-10-independent regulator of mucosal homeostasis via IL-12p40.

NFIL3-deficient mice develop microbiota-dependent, IL-12/23-driven spontaneous colitis.

The p110δ subunit of class IA PI3K modulates signaling in innate immune cells. We previously demonstrated that mice harboring a kinase-dead p110δ subunit (p110δ(KD)) develop spontaneous colitis. Macrophages contributed to the Th1/Th17 cytokine bias in p110δ(KD) mice through increased IL-12 and IL-23 expression. In this study, we show that the enteric microbiota is required for colitis development in germfree p110δ(KD) mice. Colonic tissue and macrophages from p110δ(KD) mice produce significantly less IL-10 compared with wild-type mice. p110δ(KD) APCs cocultured with naive CD4+ Ag-specific T cells also produce significantly less IL-10 and induce more IFN-γ- and IL-17A-producing CD4+ T cells compared with wild-type APCs. Illustrating the importance of APC-T cell interactions in colitis pathogenesis in vivo, Rag1(-/-)/p110δ(KD) mice develop mild colonic inflammation and produced more colonic IL-12p40 compared with Rag1(-/-) mice. However, CD4+ CD45RB(high/low) T cell Rag1(-/-)/p110δ(KD) recipient mice develop severe colitis with increased percentages of IFN-γ- and IL-17A-producing lamina propria CD3+D4+ T cells compared with Rag1(-/-) recipient mice. Intestinal tissue samples from patients with Crohn's disease reveal significantly lower expression of PIK3CD compared with intestinal samples from non-inflammatory bowel disease control subjects (p < 0.05). PIK3CD expression inversely correlates with the ratio of IL12B:IL10 expression. In conclusion, the PI3K subunit p110δ controls homeostatic APC-T cell interactions by altering the balance between IL-10 and IL-12/23. Defects in p110δ expression and/or function may underlie the pathogenesis of human inflammatory bowel disease and lead to new therapeutic strategies.

Innate PI3K p110δ regulates Th1/Th17 development and microbiota-dependent colitis.

Heme oxygenase-1 (HO-1) and its enzymatic by-product carbon monoxide (CO) have emerged as important regulators of acute and chronic inflammation. Mechanisms underlying their anti-inflammatory effects are only partially understood. In this addendum, we summarize current understanding of the role of the HO-1/CO pathway in regulation of intestinal inflammation with a focus on innate immune function. In particular, we highlight our recent findings that HO-1 and CO ameliorate intestinal inflammation through promotion of bacterial clearance. Our work and that of many others support further investigation of this global homeostatic pathway in the human inflammatory bowel diseases (IBDs).

Heme oxygenase-1 and carbon monoxide regulate intestinal homeostasis and mucosal immune responses to the enteric microbiota.

Infliximab Re-treatment in Inflammatory Bowel Disease: A Single-Center Routine Clinical Experience.

A major challenge in biology is determining how evolutionarily novel characters originate; however, mechanistic explanations for the origin of new characters are almost completely unknown. The evolution of pregnancy is an excellent system in which to study the origin of novelties because mammals preserve stages in the transition from egg laying to live birth. To determine the molecular bases of this transition, we characterized the pregnant/gravid uterine transcriptome from tetrapods to trace the evolutionary history of uterine gene expression. We show that thousands of genes evolved endometrial expression during the origins of mammalian pregnancy, including genes that mediate maternal-fetal communication and immunotolerance. Furthermore, thousands of cis-regulatory elements that mediate decidualization and cell-type identity in decidualized stromal cells are derived from ancient mammalian transposable elements (TEs). Our results indicate that one of the defining mammalian novelties evolved from DNA sequences derived from ancient mammalian TEs co-opted into hormone-responsive regulatory elements distributed throughout the genome.

Shehzad Z. Sheikh

Center for Gastrointestinal Biology and Disease,
Department of Genetics,
Curriculum in Genetics and Molecular Biology

University of North Carolina at Chapel Hill

Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4⁺CD45RB^high T Cells into Immunodeficient Mice

Shehzad Z. Sheikh

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Center for Gastrointestinal Biology and Disease,Department of Genetics,Curriculum in Genetics and Molecular Biology

University of North Carolina at Chapel Hill

Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice

Center for Gastrointestinal Biology and Disease,
Department of Genetics,
Curriculum in Genetics and Molecular Biology

Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4⁺CD45RB^high T Cells into Immunodeficient Mice