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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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Characterization of the colitis in Socs1−/−Rag2−/− mice.(a) Histological scores of the colitis of 16-week-old Socs1−/−Rag2−/− mice treated with or without antibiotics for 2 weeks from 14 weeks of age (n=3). The horizontal lines indicate the mean values. (b) Histological scores of the colitis of Socs1−/−Rag2−/− mice (black circles, n=7), Ifng−/−Socs1−/−Rag2−/− mice (black triangles, n=14), Ifng−/−Rag2−/− mice (white circles, n=5), Il23a−/−Socs1−/−Rag2−/− mice (black diamonds, n=5), Il23a−/−Rag2−/− mice (white diamonds, n=3) and Ifng−/−Socs1−/− mice (white triangles, n=5) at 9 weeks of age. The horizontal lines indicate the mean values. (c) Macroscopic and microscopic observations of the colons of Socs1−/−Rag2−/− mice with or without Treg transfer. CD4+CD25high T cells (2×105 cells) sorted from WT mice were transferred at 10 weeks of age. The mice were killed 6 weeks after the transfer. Representative data are shown. Scale bar, 200 μm. (d) Representative histopathology of the colons of Socs1−/−Rag2−/− mice transferred with Tregs sorted from WT (Il10+/+) and Il10−/− mice. Scale bar, 100 μm (upper panel). The reconstitution of Tregs confirmed by flow cytometry (lower panel). Spleens were removed from Socs1−/−Rag2−/− mice without Treg transfer (lower left) or 6 weeks after the transfer with the indicated Tregs (lower middle and right), and the frequencies of CD4+ and Foxp3+ cells among TER119−CD11c− cells gated on particular forward and side scatter were analysed. At 6 weeks after the transfer, nearly 40% of the CD4+ cells expressed Foxp3, and the frequency was similar between the Il10+/+ and Il10−/− Treg-transferred group. (e) Histological scores of the colitis of 16-week-old Socs1−/−Rag2−/− mice without transfer (black circles, n=3), transferred with Il10+/+ Tregs (black diamonds, n=3) and transferred with Il10−/− Tregs (black triangles, n=2) is shown. The horizontal lines indicate the mean values.
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f2: Characterization of the colitis in Socs1−/−Rag2−/− mice.(a) Histological scores of the colitis of 16-week-old Socs1−/−Rag2−/− mice treated with or without antibiotics for 2 weeks from 14 weeks of age (n=3). The horizontal lines indicate the mean values. (b) Histological scores of the colitis of Socs1−/−Rag2−/− mice (black circles, n=7), Ifng−/−Socs1−/−Rag2−/− mice (black triangles, n=14), Ifng−/−Rag2−/− mice (white circles, n=5), Il23a−/−Socs1−/−Rag2−/− mice (black diamonds, n=5), Il23a−/−Rag2−/− mice (white diamonds, n=3) and Ifng−/−Socs1−/− mice (white triangles, n=5) at 9 weeks of age. The horizontal lines indicate the mean values. (c) Macroscopic and microscopic observations of the colons of Socs1−/−Rag2−/− mice with or without Treg transfer. CD4+CD25high T cells (2×105 cells) sorted from WT mice were transferred at 10 weeks of age. The mice were killed 6 weeks after the transfer. Representative data are shown. Scale bar, 200 μm. (d) Representative histopathology of the colons of Socs1−/−Rag2−/− mice transferred with Tregs sorted from WT (Il10+/+) and Il10−/− mice. Scale bar, 100 μm (upper panel). The reconstitution of Tregs confirmed by flow cytometry (lower panel). Spleens were removed from Socs1−/−Rag2−/− mice without Treg transfer (lower left) or 6 weeks after the transfer with the indicated Tregs (lower middle and right), and the frequencies of CD4+ and Foxp3+ cells among TER119−CD11c− cells gated on particular forward and side scatter were analysed. At 6 weeks after the transfer, nearly 40% of the CD4+ cells expressed Foxp3, and the frequency was similar between the Il10+/+ and Il10−/− Treg-transferred group. (e) Histological scores of the colitis of 16-week-old Socs1−/−Rag2−/− mice without transfer (black circles, n=3), transferred with Il10+/+ Tregs (black diamonds, n=3) and transferred with Il10−/− Tregs (black triangles, n=2) is shown. The horizontal lines indicate the mean values.

Mentions: Socs1−/−Rag2−/− mice treated with broad-spectrum antibiotics from 6 weeks of age never developed colitis even at 9 weeks of age. Furthermore, colitis was markedly improved by antibiotic treatment even after it had developed (Fig. 2a). These observations suggest that Socs1−/− intestinal innate immune cells were highly activated by intestinal commensal bacteria, resulting in the production of inflammatory cytokines, which leads to the development of spontaneous colitis.


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)

Characterization of the colitis in Socs1−/−Rag2−/− mice.(a) Histological scores of the colitis of 16-week-old Socs1−/−Rag2−/− mice treated with or without antibiotics for 2 weeks from 14 weeks of age (n=3). The horizontal lines indicate the mean values. (b) Histological scores of the colitis of Socs1−/−Rag2−/− mice (black circles, n=7), Ifng−/−Socs1−/−Rag2−/− mice (black triangles, n=14), Ifng−/−Rag2−/− mice (white circles, n=5), Il23a−/−Socs1−/−Rag2−/− mice (black diamonds, n=5), Il23a−/−Rag2−/− mice (white diamonds, n=3) and Ifng−/−Socs1−/− mice (white triangles, n=5) at 9 weeks of age. The horizontal lines indicate the mean values. (c) Macroscopic and microscopic observations of the colons of Socs1−/−Rag2−/− mice with or without Treg transfer. CD4+CD25high T cells (2×105 cells) sorted from WT mice were transferred at 10 weeks of age. The mice were killed 6 weeks after the transfer. Representative data are shown. Scale bar, 200 μm. (d) Representative histopathology of the colons of Socs1−/−Rag2−/− mice transferred with Tregs sorted from WT (Il10+/+) and Il10−/− mice. Scale bar, 100 μm (upper panel). The reconstitution of Tregs confirmed by flow cytometry (lower panel). Spleens were removed from Socs1−/−Rag2−/− mice without Treg transfer (lower left) or 6 weeks after the transfer with the indicated Tregs (lower middle and right), and the frequencies of CD4+ and Foxp3+ cells among TER119−CD11c− cells gated on particular forward and side scatter were analysed. At 6 weeks after the transfer, nearly 40% of the CD4+ cells expressed Foxp3, and the frequency was similar between the Il10+/+ and Il10−/− Treg-transferred group. (e) Histological scores of the colitis of 16-week-old Socs1−/−Rag2−/− mice without transfer (black circles, n=3), transferred with Il10+/+ Tregs (black diamonds, n=3) and transferred with Il10−/− Tregs (black triangles, n=2) is shown. The horizontal lines indicate the mean values.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Characterization of the colitis in Socs1−/−Rag2−/− mice.(a) Histological scores of the colitis of 16-week-old Socs1−/−Rag2−/− mice treated with or without antibiotics for 2 weeks from 14 weeks of age (n=3). The horizontal lines indicate the mean values. (b) Histological scores of the colitis of Socs1−/−Rag2−/− mice (black circles, n=7), Ifng−/−Socs1−/−Rag2−/− mice (black triangles, n=14), Ifng−/−Rag2−/− mice (white circles, n=5), Il23a−/−Socs1−/−Rag2−/− mice (black diamonds, n=5), Il23a−/−Rag2−/− mice (white diamonds, n=3) and Ifng−/−Socs1−/− mice (white triangles, n=5) at 9 weeks of age. The horizontal lines indicate the mean values. (c) Macroscopic and microscopic observations of the colons of Socs1−/−Rag2−/− mice with or without Treg transfer. CD4+CD25high T cells (2×105 cells) sorted from WT mice were transferred at 10 weeks of age. The mice were killed 6 weeks after the transfer. Representative data are shown. Scale bar, 200 μm. (d) Representative histopathology of the colons of Socs1−/−Rag2−/− mice transferred with Tregs sorted from WT (Il10+/+) and Il10−/− mice. Scale bar, 100 μm (upper panel). The reconstitution of Tregs confirmed by flow cytometry (lower panel). Spleens were removed from Socs1−/−Rag2−/− mice without Treg transfer (lower left) or 6 weeks after the transfer with the indicated Tregs (lower middle and right), and the frequencies of CD4+ and Foxp3+ cells among TER119−CD11c− cells gated on particular forward and side scatter were analysed. At 6 weeks after the transfer, nearly 40% of the CD4+ cells expressed Foxp3, and the frequency was similar between the Il10+/+ and Il10−/− Treg-transferred group. (e) Histological scores of the colitis of 16-week-old Socs1−/−Rag2−/− mice without transfer (black circles, n=3), transferred with Il10+/+ Tregs (black diamonds, n=3) and transferred with Il10−/− Tregs (black triangles, n=2) is shown. The horizontal lines indicate the mean values.
Mentions: Socs1−/−Rag2−/− mice treated with broad-spectrum antibiotics from 6 weeks of age never developed colitis even at 9 weeks of age. Furthermore, colitis was markedly improved by antibiotic treatment even after it had developed (Fig. 2a). These observations suggest that Socs1−/− intestinal innate immune cells were highly activated by intestinal commensal bacteria, resulting in the production of inflammatory cytokines, which leads to the development of spontaneous colitis.

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