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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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PGE2-mediated immunosuppression is indispensable for Rag2−/− but not for WT mice to avoid intestinal inflammation.(a) Mice (WT (C57BL/6J) and Rag2−/−) were fed with or without 40 μg ml−1 of indomethacin in drinking water for 3 days. The levels of PGE2 were determined by ELISA. (b) WT (C57BL/6J) and Rag2−/− mice were continuously administered 40 μg ml−1 of indomethacin in drinking water. Upper panels: Representative macroscopic and microscopic observations of the large intestines of the indomethacin-administered WT (upper intestine in macroscopic image and lower left section in microscopic image) and Rag2−/− mice (lower intestine in macroscopic image and lower right section in microscopic image). Scale bar, 200 μm. Lower panels: The body weights (lower left) and survival rates (lower right) of WT (black line) and Rag2−/− mice (red line) are shown; n=4 for each group. Error bars represent ±s.d. (c) RNAs were extracted from the proximal colons of the indomethacin-administered WT (C57BL/6J) and Rag2−/− mice on days 0, 4 and 6 (n=2 for each day), and the indicated gene expression was analysed by RT-PCR. (d) The body weights of Rag2−/− mice administered with indomethacin alone (red line) and indomethacin plus PTGER4 agonist (black line); n=3 for each group. Error bars represent ±s.d. (e) Microscopic observations of the caecum and survival rates of indomethacin-administered Rag2−/− mice treated with antibiotics (upper right image and black line in lower panel) or without antibiotics (upper left image and red line in lower panel). Scale bar, 200 μm; n=3 for each group. (f) CD4+CD25high cells (Tregs, 2×105 cells) were transferred to 4-week-old Rag2−/− mice. At 4 weeks after the transfer, mice were fed with indomethacin for 8 days. Microscopic observations of proximal colons and body weights of indomethacin-administered Rag2−/− mice transferred with Tregs (upper right image and black line in lower panel) or without Tregs (upper left image and red line in lower panel) are shown; n=3 for each group. Scale bar, 200 μm. Error bars represent ±s.d.
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f4: PGE2-mediated immunosuppression is indispensable for Rag2−/− but not for WT mice to avoid intestinal inflammation.(a) Mice (WT (C57BL/6J) and Rag2−/−) were fed with or without 40 μg ml−1 of indomethacin in drinking water for 3 days. The levels of PGE2 were determined by ELISA. (b) WT (C57BL/6J) and Rag2−/− mice were continuously administered 40 μg ml−1 of indomethacin in drinking water. Upper panels: Representative macroscopic and microscopic observations of the large intestines of the indomethacin-administered WT (upper intestine in macroscopic image and lower left section in microscopic image) and Rag2−/− mice (lower intestine in macroscopic image and lower right section in microscopic image). Scale bar, 200 μm. Lower panels: The body weights (lower left) and survival rates (lower right) of WT (black line) and Rag2−/− mice (red line) are shown; n=4 for each group. Error bars represent ±s.d. (c) RNAs were extracted from the proximal colons of the indomethacin-administered WT (C57BL/6J) and Rag2−/− mice on days 0, 4 and 6 (n=2 for each day), and the indicated gene expression was analysed by RT-PCR. (d) The body weights of Rag2−/− mice administered with indomethacin alone (red line) and indomethacin plus PTGER4 agonist (black line); n=3 for each group. Error bars represent ±s.d. (e) Microscopic observations of the caecum and survival rates of indomethacin-administered Rag2−/− mice treated with antibiotics (upper right image and black line in lower panel) or without antibiotics (upper left image and red line in lower panel). Scale bar, 200 μm; n=3 for each group. (f) CD4+CD25high cells (Tregs, 2×105 cells) were transferred to 4-week-old Rag2−/− mice. At 4 weeks after the transfer, mice were fed with indomethacin for 8 days. Microscopic observations of proximal colons and body weights of indomethacin-administered Rag2−/− mice transferred with Tregs (upper right image and black line in lower panel) or without Tregs (upper left image and red line in lower panel) are shown; n=3 for each group. Scale bar, 200 μm. Error bars represent ±s.d.

Mentions: Next, to confirm that PGE2 has a regulatory role in the intestine in the absence of Tregs, we continuously administered the non-selective COX inhibitor indomethacin to WT (Rag2+/+) and Rag2−/− mice in the drinking water. This treatment effectively suppressed the production of PGE2 in the colons of mice of both genotypes (Fig. 4a). Interestingly, although indomethacin-administered WT mice rarely developed symptoms, Rag2−/− mice showed a high susceptibility to indomethacin, and developed diarrhoea and weight loss because of severe inflammation in the caecum and colon (Fig. 4b) accompanied by elevated levels of inflammatory cytokines (Fig. 4c), whereas WT mice developed almost no inflammatory changes in the intestine. When a PTGER4 agonist was administered together with indomethacin, Rag2−/− mice did not develop colitis and wasting disease (Fig. 4d), suggesting that the decrease in PGE2/PTGER4 signalling is the direct cause of indomethacin-induced inflammation in Rag2−/− mice.


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)

PGE2-mediated immunosuppression is indispensable for Rag2−/− but not for WT mice to avoid intestinal inflammation.(a) Mice (WT (C57BL/6J) and Rag2−/−) were fed with or without 40 μg ml−1 of indomethacin in drinking water for 3 days. The levels of PGE2 were determined by ELISA. (b) WT (C57BL/6J) and Rag2−/− mice were continuously administered 40 μg ml−1 of indomethacin in drinking water. Upper panels: Representative macroscopic and microscopic observations of the large intestines of the indomethacin-administered WT (upper intestine in macroscopic image and lower left section in microscopic image) and Rag2−/− mice (lower intestine in macroscopic image and lower right section in microscopic image). Scale bar, 200 μm. Lower panels: The body weights (lower left) and survival rates (lower right) of WT (black line) and Rag2−/− mice (red line) are shown; n=4 for each group. Error bars represent ±s.d. (c) RNAs were extracted from the proximal colons of the indomethacin-administered WT (C57BL/6J) and Rag2−/− mice on days 0, 4 and 6 (n=2 for each day), and the indicated gene expression was analysed by RT-PCR. (d) The body weights of Rag2−/− mice administered with indomethacin alone (red line) and indomethacin plus PTGER4 agonist (black line); n=3 for each group. Error bars represent ±s.d. (e) Microscopic observations of the caecum and survival rates of indomethacin-administered Rag2−/− mice treated with antibiotics (upper right image and black line in lower panel) or without antibiotics (upper left image and red line in lower panel). Scale bar, 200 μm; n=3 for each group. (f) CD4+CD25high cells (Tregs, 2×105 cells) were transferred to 4-week-old Rag2−/− mice. At 4 weeks after the transfer, mice were fed with indomethacin for 8 days. Microscopic observations of proximal colons and body weights of indomethacin-administered Rag2−/− mice transferred with Tregs (upper right image and black line in lower panel) or without Tregs (upper left image and red line in lower panel) are shown; n=3 for each group. Scale bar, 200 μm. Error bars represent ±s.d.
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f4: PGE2-mediated immunosuppression is indispensable for Rag2−/− but not for WT mice to avoid intestinal inflammation.(a) Mice (WT (C57BL/6J) and Rag2−/−) were fed with or without 40 μg ml−1 of indomethacin in drinking water for 3 days. The levels of PGE2 were determined by ELISA. (b) WT (C57BL/6J) and Rag2−/− mice were continuously administered 40 μg ml−1 of indomethacin in drinking water. Upper panels: Representative macroscopic and microscopic observations of the large intestines of the indomethacin-administered WT (upper intestine in macroscopic image and lower left section in microscopic image) and Rag2−/− mice (lower intestine in macroscopic image and lower right section in microscopic image). Scale bar, 200 μm. Lower panels: The body weights (lower left) and survival rates (lower right) of WT (black line) and Rag2−/− mice (red line) are shown; n=4 for each group. Error bars represent ±s.d. (c) RNAs were extracted from the proximal colons of the indomethacin-administered WT (C57BL/6J) and Rag2−/− mice on days 0, 4 and 6 (n=2 for each day), and the indicated gene expression was analysed by RT-PCR. (d) The body weights of Rag2−/− mice administered with indomethacin alone (red line) and indomethacin plus PTGER4 agonist (black line); n=3 for each group. Error bars represent ±s.d. (e) Microscopic observations of the caecum and survival rates of indomethacin-administered Rag2−/− mice treated with antibiotics (upper right image and black line in lower panel) or without antibiotics (upper left image and red line in lower panel). Scale bar, 200 μm; n=3 for each group. (f) CD4+CD25high cells (Tregs, 2×105 cells) were transferred to 4-week-old Rag2−/− mice. At 4 weeks after the transfer, mice were fed with indomethacin for 8 days. Microscopic observations of proximal colons and body weights of indomethacin-administered Rag2−/− mice transferred with Tregs (upper right image and black line in lower panel) or without Tregs (upper left image and red line in lower panel) are shown; n=3 for each group. Scale bar, 200 μm. Error bars represent ±s.d.
Mentions: Next, to confirm that PGE2 has a regulatory role in the intestine in the absence of Tregs, we continuously administered the non-selective COX inhibitor indomethacin to WT (Rag2+/+) and Rag2−/− mice in the drinking water. This treatment effectively suppressed the production of PGE2 in the colons of mice of both genotypes (Fig. 4a). Interestingly, although indomethacin-administered WT mice rarely developed symptoms, Rag2−/− mice showed a high susceptibility to indomethacin, and developed diarrhoea and weight loss because of severe inflammation in the caecum and colon (Fig. 4b) accompanied by elevated levels of inflammatory cytokines (Fig. 4c), whereas WT mice developed almost no inflammatory changes in the intestine. When a PTGER4 agonist was administered together with indomethacin, Rag2−/− mice did not develop colitis and wasting disease (Fig. 4d), suggesting that the decrease in PGE2/PTGER4 signalling is the direct cause of indomethacin-induced inflammation in Rag2−/− mice.

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