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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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Socs1−/−Rag2−/− mice develop spontaneous colitis.(a) The survival curves of Socs1−/− (black, n=5), Socs1−/−Tcra−/− (red, n=14), Socs1−/−Rag2−/− (blue, n=12), Socs1-KOTg (green, n=6) and Ifng−/−Socs1−/− (green, dotted, n=10) mice. (b) Rag2−/− and Socs1−/−Rag2−/− mice (8-week-old; upper panel). Representative macroscopic observations of the colons of 9-week-old Rag2−/− and Socs1−/−Rag2−/− mice (lower panel). (c) Representative histopathology of the colons of Rag2−/− (upper left panel) and Socs1−/−Rag2−/− mice (other five panels) at 9 weeks of age stained with haematoxylin and eosin. Scale bar, 100 μm. (d) The histological scores of colitis for Rag2−/− (n=9) and Socs1−/−Rag2−/− (n=8) mice at 9 weeks of age. The horizontal lines indicate the mean values. (e) Flow cytometric analyses showing the proportions of CD11bhigh and natural killer (NK) (DX5+) cells among CD45+TER119− cells (upper), Gr-1+ and F4/80+ cells among CD11b+ cells (middle) and CD11c+ and F4/80+ cells among CD11b+ cells (lower) in the spleens of Rag2−/− and Socs1−/−Rag2−/− mice. Data are representative of three independent experiments. (f) Fluorescence immunohistochemistry showing the infiltration of CD45+ cells (red) into the colonic lamina propria of Rag2−/− (upper left panel) and Socs1−/−Rag2−/− mice (upper right panel). The infiltrating CD45+ cells were predominantly CD11b+ cells (green), although NK1.1+ cells (red) were also significantly increased (lower panels). Nuclei of cells are stained with Hoechst 33342 dye (blue). Data are representative of three independent experiments using samples from different mice. Scale bar, 100 μm. (g) RNAs were extracted from the colons of 9-week-old Rag2−/− and Socs1−/−Rag2−/− mice, and the indicated gene expression was analysed by RT-PCR. Three mice per group are shown. Data are representative of three independent experiments using different samples from one to three mice per group. (h) CD11bhighNK1.1− and NK1.1+ cells were sorted by FACSAria from the spleens of Rag2−/− and Socs1−/−Rag2−/− mice, and RNA was purified from the cells. The relative expression levels of the indicated genes were normalized against Hprt1 using Ct values determined by quantitative real-time RT-PCR. Error bars represent +s.d. of triplicate measurements for each sample. *P<0.05 and **P<0.01 compared with Rag2−/− cells. Data are representative of two independent experiments. (i) Proteins were extracted from the colons of 9-week-old Rag2−/− and Socs1−/−Rag2−/− mice, and western blot analyses were performed using indicated Abs. Three mice per group are shown. PY, tyrosine phosphorylated; PS, serine phosphorylated. Data are representative of two independent experiments using different samples from two to three mice per group. ND, not determined.
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f1: Socs1−/−Rag2−/− mice develop spontaneous colitis.(a) The survival curves of Socs1−/− (black, n=5), Socs1−/−Tcra−/− (red, n=14), Socs1−/−Rag2−/− (blue, n=12), Socs1-KOTg (green, n=6) and Ifng−/−Socs1−/− (green, dotted, n=10) mice. (b) Rag2−/− and Socs1−/−Rag2−/− mice (8-week-old; upper panel). Representative macroscopic observations of the colons of 9-week-old Rag2−/− and Socs1−/−Rag2−/− mice (lower panel). (c) Representative histopathology of the colons of Rag2−/− (upper left panel) and Socs1−/−Rag2−/− mice (other five panels) at 9 weeks of age stained with haematoxylin and eosin. Scale bar, 100 μm. (d) The histological scores of colitis for Rag2−/− (n=9) and Socs1−/−Rag2−/− (n=8) mice at 9 weeks of age. The horizontal lines indicate the mean values. (e) Flow cytometric analyses showing the proportions of CD11bhigh and natural killer (NK) (DX5+) cells among CD45+TER119− cells (upper), Gr-1+ and F4/80+ cells among CD11b+ cells (middle) and CD11c+ and F4/80+ cells among CD11b+ cells (lower) in the spleens of Rag2−/− and Socs1−/−Rag2−/− mice. Data are representative of three independent experiments. (f) Fluorescence immunohistochemistry showing the infiltration of CD45+ cells (red) into the colonic lamina propria of Rag2−/− (upper left panel) and Socs1−/−Rag2−/− mice (upper right panel). The infiltrating CD45+ cells were predominantly CD11b+ cells (green), although NK1.1+ cells (red) were also significantly increased (lower panels). Nuclei of cells are stained with Hoechst 33342 dye (blue). Data are representative of three independent experiments using samples from different mice. Scale bar, 100 μm. (g) RNAs were extracted from the colons of 9-week-old Rag2−/− and Socs1−/−Rag2−/− mice, and the indicated gene expression was analysed by RT-PCR. Three mice per group are shown. Data are representative of three independent experiments using different samples from one to three mice per group. (h) CD11bhighNK1.1− and NK1.1+ cells were sorted by FACSAria from the spleens of Rag2−/− and Socs1−/−Rag2−/− mice, and RNA was purified from the cells. The relative expression levels of the indicated genes were normalized against Hprt1 using Ct values determined by quantitative real-time RT-PCR. Error bars represent +s.d. of triplicate measurements for each sample. *P<0.05 and **P<0.01 compared with Rag2−/− cells. Data are representative of two independent experiments. (i) Proteins were extracted from the colons of 9-week-old Rag2−/− and Socs1−/−Rag2−/− mice, and western blot analyses were performed using indicated Abs. Three mice per group are shown. PY, tyrosine phosphorylated; PS, serine phosphorylated. Data are representative of two independent experiments using different samples from two to three mice per group. ND, not determined.

Mentions: Socs1−/− mice die shortly after birth as result of severe systemic inflammation8. It has been shown that early lethality can be reverted by crossing with Ifng−/− mice, Tcra−/− mice or Rag2−/− mice, or by restoring SOCS1 expression in T and B cells by crossing with T- and B-cell-specific Socs1 Tg mice (Socs1-KOTg mice)891011. Figure 1a shows the course of survival of various Socs1−/− mice in our facility. These data suggest that dysregulation of IFNγ signalling and activation of lymphocytes are the main causes of the early lethality in Socs1−/− mice. We have previously shown that Socs1−/−Tcra−/− mice developed more severe colitis than Tcra−/− mice11. We suspected that SOCS1 deficiency in T cells might contribute to the development of colitis; however, we later found that Socs1-KOTg mice, in which SOCS1 expression is restored in T cells, also developed mild colitis with age12. Furthermore, we found that Socs1−/−Rag2−/− mice developed fatal colitis (Fig. 1). These observations suggest that SOCS1 expression in cells other than T cells is important in suppression of 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)

Socs1−/−Rag2−/− mice develop spontaneous colitis.(a) The survival curves of Socs1−/− (black, n=5), Socs1−/−Tcra−/− (red, n=14), Socs1−/−Rag2−/− (blue, n=12), Socs1-KOTg (green, n=6) and Ifng−/−Socs1−/− (green, dotted, n=10) mice. (b) Rag2−/− and Socs1−/−Rag2−/− mice (8-week-old; upper panel). Representative macroscopic observations of the colons of 9-week-old Rag2−/− and Socs1−/−Rag2−/− mice (lower panel). (c) Representative histopathology of the colons of Rag2−/− (upper left panel) and Socs1−/−Rag2−/− mice (other five panels) at 9 weeks of age stained with haematoxylin and eosin. Scale bar, 100 μm. (d) The histological scores of colitis for Rag2−/− (n=9) and Socs1−/−Rag2−/− (n=8) mice at 9 weeks of age. The horizontal lines indicate the mean values. (e) Flow cytometric analyses showing the proportions of CD11bhigh and natural killer (NK) (DX5+) cells among CD45+TER119− cells (upper), Gr-1+ and F4/80+ cells among CD11b+ cells (middle) and CD11c+ and F4/80+ cells among CD11b+ cells (lower) in the spleens of Rag2−/− and Socs1−/−Rag2−/− mice. Data are representative of three independent experiments. (f) Fluorescence immunohistochemistry showing the infiltration of CD45+ cells (red) into the colonic lamina propria of Rag2−/− (upper left panel) and Socs1−/−Rag2−/− mice (upper right panel). The infiltrating CD45+ cells were predominantly CD11b+ cells (green), although NK1.1+ cells (red) were also significantly increased (lower panels). Nuclei of cells are stained with Hoechst 33342 dye (blue). Data are representative of three independent experiments using samples from different mice. Scale bar, 100 μm. (g) RNAs were extracted from the colons of 9-week-old Rag2−/− and Socs1−/−Rag2−/− mice, and the indicated gene expression was analysed by RT-PCR. Three mice per group are shown. Data are representative of three independent experiments using different samples from one to three mice per group. (h) CD11bhighNK1.1− and NK1.1+ cells were sorted by FACSAria from the spleens of Rag2−/− and Socs1−/−Rag2−/− mice, and RNA was purified from the cells. The relative expression levels of the indicated genes were normalized against Hprt1 using Ct values determined by quantitative real-time RT-PCR. Error bars represent +s.d. of triplicate measurements for each sample. *P<0.05 and **P<0.01 compared with Rag2−/− cells. Data are representative of two independent experiments. (i) Proteins were extracted from the colons of 9-week-old Rag2−/− and Socs1−/−Rag2−/− mice, and western blot analyses were performed using indicated Abs. Three mice per group are shown. PY, tyrosine phosphorylated; PS, serine phosphorylated. Data are representative of two independent experiments using different samples from two to three mice per group. ND, not determined.
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f1: Socs1−/−Rag2−/− mice develop spontaneous colitis.(a) The survival curves of Socs1−/− (black, n=5), Socs1−/−Tcra−/− (red, n=14), Socs1−/−Rag2−/− (blue, n=12), Socs1-KOTg (green, n=6) and Ifng−/−Socs1−/− (green, dotted, n=10) mice. (b) Rag2−/− and Socs1−/−Rag2−/− mice (8-week-old; upper panel). Representative macroscopic observations of the colons of 9-week-old Rag2−/− and Socs1−/−Rag2−/− mice (lower panel). (c) Representative histopathology of the colons of Rag2−/− (upper left panel) and Socs1−/−Rag2−/− mice (other five panels) at 9 weeks of age stained with haematoxylin and eosin. Scale bar, 100 μm. (d) The histological scores of colitis for Rag2−/− (n=9) and Socs1−/−Rag2−/− (n=8) mice at 9 weeks of age. The horizontal lines indicate the mean values. (e) Flow cytometric analyses showing the proportions of CD11bhigh and natural killer (NK) (DX5+) cells among CD45+TER119− cells (upper), Gr-1+ and F4/80+ cells among CD11b+ cells (middle) and CD11c+ and F4/80+ cells among CD11b+ cells (lower) in the spleens of Rag2−/− and Socs1−/−Rag2−/− mice. Data are representative of three independent experiments. (f) Fluorescence immunohistochemistry showing the infiltration of CD45+ cells (red) into the colonic lamina propria of Rag2−/− (upper left panel) and Socs1−/−Rag2−/− mice (upper right panel). The infiltrating CD45+ cells were predominantly CD11b+ cells (green), although NK1.1+ cells (red) were also significantly increased (lower panels). Nuclei of cells are stained with Hoechst 33342 dye (blue). Data are representative of three independent experiments using samples from different mice. Scale bar, 100 μm. (g) RNAs were extracted from the colons of 9-week-old Rag2−/− and Socs1−/−Rag2−/− mice, and the indicated gene expression was analysed by RT-PCR. Three mice per group are shown. Data are representative of three independent experiments using different samples from one to three mice per group. (h) CD11bhighNK1.1− and NK1.1+ cells were sorted by FACSAria from the spleens of Rag2−/− and Socs1−/−Rag2−/− mice, and RNA was purified from the cells. The relative expression levels of the indicated genes were normalized against Hprt1 using Ct values determined by quantitative real-time RT-PCR. Error bars represent +s.d. of triplicate measurements for each sample. *P<0.05 and **P<0.01 compared with Rag2−/− cells. Data are representative of two independent experiments. (i) Proteins were extracted from the colons of 9-week-old Rag2−/− and Socs1−/−Rag2−/− mice, and western blot analyses were performed using indicated Abs. Three mice per group are shown. PY, tyrosine phosphorylated; PS, serine phosphorylated. Data are representative of two independent experiments using different samples from two to three mice per group. ND, not determined.
Mentions: Socs1−/− mice die shortly after birth as result of severe systemic inflammation8. It has been shown that early lethality can be reverted by crossing with Ifng−/− mice, Tcra−/− mice or Rag2−/− mice, or by restoring SOCS1 expression in T and B cells by crossing with T- and B-cell-specific Socs1 Tg mice (Socs1-KOTg mice)891011. Figure 1a shows the course of survival of various Socs1−/− mice in our facility. These data suggest that dysregulation of IFNγ signalling and activation of lymphocytes are the main causes of the early lethality in Socs1−/− mice. We have previously shown that Socs1−/−Tcra−/− mice developed more severe colitis than Tcra−/− mice11. We suspected that SOCS1 deficiency in T cells might contribute to the development of colitis; however, we later found that Socs1-KOTg mice, in which SOCS1 expression is restored in T cells, also developed mild colitis with age12. Furthermore, we found that Socs1−/−Rag2−/− mice developed fatal colitis (Fig. 1). These observations suggest that SOCS1 expression in cells other than T cells is important in suppression of 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