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Prostaglandin E2 and SOCS1 have a role in intestinal immune tolerance.

Chinen T, Komai K, Muto G, Morita R, Inoue N, Yoshida H, Sekiya T, Yoshida R, Nakamura K, Takayanagi R, Yoshimura A - Nat Commun (2011)

Bottom Line: Additionally, we find an essential role for prostaglandin E2 (PGE2) in the maintenance of tolerance within the intestine in the absence of Tregs.Socs1(-/-) dendritic cells are resistant to PGE2-mediated immunosuppression because of dysregulated cytokine signalling.Thus, we propose that SOCS1 and PGE2, potentially interacting together, act as an alternative intestinal tolerance mechanism distinct from IL-10 and Tregs.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

ABSTRACT
Interleukin 10 (IL-10) and regulatory T cells (Tregs) maintain tolerance to intestinal microorganisms. However, Il10(-/-)Rag2(-/-) mice, which lack IL-10 and Tregs, remain healthy, suggesting the existence of other mechanisms of tolerance. Here, we identify suppressor of cytokine signalling 1 (SOCS1) as an essential mediator of immune tolerance in the intestine. Socs1(-/-)Rag2(-/-) mice develop severe colitis, which can be prevented by the reduction of microbiota and the transfer of IL-10-sufficient Tregs. Additionally, we find an essential role for prostaglandin E2 (PGE2) in the maintenance of tolerance within the intestine in the absence of Tregs. Socs1(-/-) dendritic cells are resistant to PGE2-mediated immunosuppression because of dysregulated cytokine signalling. Thus, we propose that SOCS1 and PGE2, potentially interacting together, act as an alternative intestinal tolerance mechanism distinct from IL-10 and Tregs.

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A model for SOCS1-dependent and -independent mechanism of intestinal tolerance.Tolerance to commensal bacteria is regulated by two independent pathways: PGE2-cAMP and Treg-IL-10. Inflammatory cytokines, especially IFNγ, antagonize PGE2-cAMP-mediated suppression for Toll-like receptor signalling. SOCS1 negatively regulates IFNγ signalling, thus maintaining the PGE2-cAMP-mediated tolerance.
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f7: A model for SOCS1-dependent and -independent mechanism of intestinal tolerance.Tolerance to commensal bacteria is regulated by two independent pathways: PGE2-cAMP and Treg-IL-10. Inflammatory cytokines, especially IFNγ, antagonize PGE2-cAMP-mediated suppression for Toll-like receptor signalling. SOCS1 negatively regulates IFNγ signalling, thus maintaining the PGE2-cAMP-mediated tolerance.

Mentions: Lastly, we confirmed the relationship among SOCS1, cAMP and IL-10/Tregs (Fig. 5d). When we co-cultured Socs1+/+ BMDCs with cAMP and Tregs, the production of IL-12p70 and TNFα was intensively suppressed. The suppressive effect of Treg was diminished by anti-IL-10 Ab, indicating that Treg functioned through IL-10 in this co-culture experiment (Fig. 5d). Although immunosuppressive effect of cAMP was diminished in Socs1−/− BMDCs, Tregs potently suppressed cytokine production from Socs1−/− BMDCs in an IL-10-dependent manner (Fig. 5d). These phenomena were consistent with our in vivo observation that Tregs suppressed colitis in both Socs1−/−Rag2−/− mice and indomethacin-treated Rag2−/− mice. We found that another STAT1-activating cytokine IL-27 and the STAT6-activating cytokines, IL-4 and IL-13, also counteracted the immunosuppressive effect of cAMP in Socs1−/− BMDCs, although their effect was not as evident as that of IFNγ (Fig. 6). This may explain why IFNγ deficiency could not completely eliminate the colitis in Ifng−/−Socs1−/−Rag2−/− mice (Fig. 2b). The involvement of STAT6-activating cytokines, especially IL-13, for pathogenesis of colitis has been shown in previous studies2021. Although a recent study suggested a role of IL-13 for attenuation of production of IFNγ and IL-17, and the resultant colitis due to IL-10 deficiency22, our study here suggests a synergistic involvement of IFNγ, IL-4 and IL-13 for aggravation of colitis. Collectively, the Treg/IL-10 system seems to be more stable than the PGE2/cAMP system, as the former system was not affected by the strong cytokine signalling, especially IFNγ/STAT1 signalling, resulting from SOCS1 deficiency. The hierarchy among these suppression systems suggested by this study is shown in Figure 7.


Prostaglandin E2 and SOCS1 have a role in intestinal immune tolerance.

Chinen T, Komai K, Muto G, Morita R, Inoue N, Yoshida H, Sekiya T, Yoshida R, Nakamura K, Takayanagi R, Yoshimura A - Nat Commun (2011)

A model for SOCS1-dependent and -independent mechanism of intestinal tolerance.Tolerance to commensal bacteria is regulated by two independent pathways: PGE2-cAMP and Treg-IL-10. Inflammatory cytokines, especially IFNγ, antagonize PGE2-cAMP-mediated suppression for Toll-like receptor signalling. SOCS1 negatively regulates IFNγ signalling, thus maintaining the PGE2-cAMP-mediated tolerance.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105338&req=5

f7: A model for SOCS1-dependent and -independent mechanism of intestinal tolerance.Tolerance to commensal bacteria is regulated by two independent pathways: PGE2-cAMP and Treg-IL-10. Inflammatory cytokines, especially IFNγ, antagonize PGE2-cAMP-mediated suppression for Toll-like receptor signalling. SOCS1 negatively regulates IFNγ signalling, thus maintaining the PGE2-cAMP-mediated tolerance.
Mentions: Lastly, we confirmed the relationship among SOCS1, cAMP and IL-10/Tregs (Fig. 5d). When we co-cultured Socs1+/+ BMDCs with cAMP and Tregs, the production of IL-12p70 and TNFα was intensively suppressed. The suppressive effect of Treg was diminished by anti-IL-10 Ab, indicating that Treg functioned through IL-10 in this co-culture experiment (Fig. 5d). Although immunosuppressive effect of cAMP was diminished in Socs1−/− BMDCs, Tregs potently suppressed cytokine production from Socs1−/− BMDCs in an IL-10-dependent manner (Fig. 5d). These phenomena were consistent with our in vivo observation that Tregs suppressed colitis in both Socs1−/−Rag2−/− mice and indomethacin-treated Rag2−/− mice. We found that another STAT1-activating cytokine IL-27 and the STAT6-activating cytokines, IL-4 and IL-13, also counteracted the immunosuppressive effect of cAMP in Socs1−/− BMDCs, although their effect was not as evident as that of IFNγ (Fig. 6). This may explain why IFNγ deficiency could not completely eliminate the colitis in Ifng−/−Socs1−/−Rag2−/− mice (Fig. 2b). The involvement of STAT6-activating cytokines, especially IL-13, for pathogenesis of colitis has been shown in previous studies2021. Although a recent study suggested a role of IL-13 for attenuation of production of IFNγ and IL-17, and the resultant colitis due to IL-10 deficiency22, our study here suggests a synergistic involvement of IFNγ, IL-4 and IL-13 for aggravation of colitis. Collectively, the Treg/IL-10 system seems to be more stable than the PGE2/cAMP system, as the former system was not affected by the strong cytokine signalling, especially IFNγ/STAT1 signalling, resulting from SOCS1 deficiency. The hierarchy among these suppression systems suggested by this study is shown in Figure 7.

Bottom Line: Additionally, we find an essential role for prostaglandin E2 (PGE2) in the maintenance of tolerance within the intestine in the absence of Tregs.Socs1(-/-) dendritic cells are resistant to PGE2-mediated immunosuppression because of dysregulated cytokine signalling.Thus, we propose that SOCS1 and PGE2, potentially interacting together, act as an alternative intestinal tolerance mechanism distinct from IL-10 and Tregs.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

ABSTRACT
Interleukin 10 (IL-10) and regulatory T cells (Tregs) maintain tolerance to intestinal microorganisms. However, Il10(-/-)Rag2(-/-) mice, which lack IL-10 and Tregs, remain healthy, suggesting the existence of other mechanisms of tolerance. Here, we identify suppressor of cytokine signalling 1 (SOCS1) as an essential mediator of immune tolerance in the intestine. Socs1(-/-)Rag2(-/-) mice develop severe colitis, which can be prevented by the reduction of microbiota and the transfer of IL-10-sufficient Tregs. Additionally, we find an essential role for prostaglandin E2 (PGE2) in the maintenance of tolerance within the intestine in the absence of Tregs. Socs1(-/-) dendritic cells are resistant to PGE2-mediated immunosuppression because of dysregulated cytokine signalling. Thus, we propose that SOCS1 and PGE2, potentially interacting together, act as an alternative intestinal tolerance mechanism distinct from IL-10 and Tregs.

Show MeSH
Related in: MedlinePlus