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Specific regulation of T helper cell 1-mediated murine colitis by CEACAM1.

Iijima H, Neurath MF, Nagaishi T, Glickman JN, Nieuwenhuis EE, Nakajima A, Chen D, Fuss IJ, Utku N, Lewicki DN, Becker C, Gallagher TM, Holmes KV, Blumberg RS - J. Exp. Med. (2004)

Bottom Line: We have shown that CEACAM1 is associated with specific regulation of T helper cell (Th)1 pathways, T-bet-mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo.Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production.These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease.

View Article: PubMed Central - PubMed

Affiliation: Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

ABSTRACT
Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) is a cell surface molecule that has been proposed to negatively regulate T cell function. We have shown that CEACAM1 is associated with specific regulation of T helper cell (Th)1 pathways, T-bet-mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo. Mice treated with anti-mouse CEACAM1-specific monoclonal antibody (mAb) CC1 during the effector phase exhibited a reduced severity of trinitrobenzene sulfonic acid colitis in association with decreased interferon (IFN)-gamma production. Although oxazolone colitis has been reported as Th2 mediated, mice treated with the CC1 mAb or a CEACAM1-Fc chimeric protein exhibited a reduced severity of colitis in association with a significant reduction of IFN-gamma and T-bet activation, whereas signal transducer and activator of antigen 4 activation was unaffected. Both interleukin-4 and IFN-gamma gene-deficient mice exhibited less severe colitis induction by oxazolone. Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production. These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease.

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Effect of CEACAM1-Fc chimeric protein on the induction of oxazolone colitis. Macroscopic (a) and histologic pictures (b; ×100) of colon isolated from mice induced to develop oxazolone colitis treated with CEACAM1-Fc or a control-Fc fragment. (c) Colitis scores of colon-induced oxazolone colitis treated with CEACAM1-Fc (solid bar) or a control-Fc fragment (open bar). Mice treated with CEACAM1-Fc exhibited significant reduction in colitis scores (*, P < 0.005; **, P < 0.01). V, hyper-vascularization; M, presence of mononuclear cells; H, epithelial cell hyperplasia; I, epithelial injury; G, presence of granulocytes; T, total score. (d) Th1 and Th2 cytokine production from LPLs was analyzed by ELISA of mice with oxazolone colitis treated either with CEACAM1-Fc (solid bars) or control-Fc fragment (open bars). Suppression of IFN-γ was significant (**, P < 0.01). Data are shown as mean values ± SEM from four independent experiments.
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fig4: Effect of CEACAM1-Fc chimeric protein on the induction of oxazolone colitis. Macroscopic (a) and histologic pictures (b; ×100) of colon isolated from mice induced to develop oxazolone colitis treated with CEACAM1-Fc or a control-Fc fragment. (c) Colitis scores of colon-induced oxazolone colitis treated with CEACAM1-Fc (solid bar) or a control-Fc fragment (open bar). Mice treated with CEACAM1-Fc exhibited significant reduction in colitis scores (*, P < 0.005; **, P < 0.01). V, hyper-vascularization; M, presence of mononuclear cells; H, epithelial cell hyperplasia; I, epithelial injury; G, presence of granulocytes; T, total score. (d) Th1 and Th2 cytokine production from LPLs was analyzed by ELISA of mice with oxazolone colitis treated either with CEACAM1-Fc (solid bars) or control-Fc fragment (open bars). Suppression of IFN-γ was significant (**, P < 0.01). Data are shown as mean values ± SEM from four independent experiments.

Mentions: Our results, as shown here, indicate that ligation of CEACAM1a with the CC1 mAb significantly suppresses colitis in association with inhibition of T cell production of IFN-γ by LPLs. However, these results do not define either the nature of the natural ligand for CEACAM1a in vivo and whether inhibition of Th1-mediated immunopathology can be caused by ligation of CEACAM1a with its natural ligand. To define the ligand for CEACAM1a in vivo, we examined the effects of a CEACAM1a-Fc fusion protein (sMHVR-Ig) encoding the extracellular portion of the mCEACAM1a-4L isoform that has been shown to homophilically ligate the CEACAM1a molecule in vitro (32). Therefore, mice were treated with either the CEACAM1a-Fc fusion protein or a control isotype–matched Fc fragment at a dose of 200 μg administered every other day for seven doses beginning at the time of skin sensitization in the oxazolone colitis model. Macroscopic assessment revealed that shortening of the colon was less severe in the mice treated with CEACAM1a-Fc compared with the mice administered the control-Fc fragment (Fig. 4 a). Similarly, histologic evidence of colitis was less pronounced in the CEACAM1a-Fc–treated group compared with the control-Fc–treated group (Fig. 4, b and c). These pathologic findings were associated with a significant decrease in IFN-γ production by LPLs from mice treated with the CEACAM1a-Fc fusion protein (Fig. 4 d). The fact that the decrease in immunopathologic injury observed occurred in association with suppression of IFN-γ production indicated that these were causally related.


Specific regulation of T helper cell 1-mediated murine colitis by CEACAM1.

Iijima H, Neurath MF, Nagaishi T, Glickman JN, Nieuwenhuis EE, Nakajima A, Chen D, Fuss IJ, Utku N, Lewicki DN, Becker C, Gallagher TM, Holmes KV, Blumberg RS - J. Exp. Med. (2004)

Effect of CEACAM1-Fc chimeric protein on the induction of oxazolone colitis. Macroscopic (a) and histologic pictures (b; ×100) of colon isolated from mice induced to develop oxazolone colitis treated with CEACAM1-Fc or a control-Fc fragment. (c) Colitis scores of colon-induced oxazolone colitis treated with CEACAM1-Fc (solid bar) or a control-Fc fragment (open bar). Mice treated with CEACAM1-Fc exhibited significant reduction in colitis scores (*, P < 0.005; **, P < 0.01). V, hyper-vascularization; M, presence of mononuclear cells; H, epithelial cell hyperplasia; I, epithelial injury; G, presence of granulocytes; T, total score. (d) Th1 and Th2 cytokine production from LPLs was analyzed by ELISA of mice with oxazolone colitis treated either with CEACAM1-Fc (solid bars) or control-Fc fragment (open bars). Suppression of IFN-γ was significant (**, P < 0.01). Data are shown as mean values ± SEM from four independent experiments.
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Related In: Results  -  Collection

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fig4: Effect of CEACAM1-Fc chimeric protein on the induction of oxazolone colitis. Macroscopic (a) and histologic pictures (b; ×100) of colon isolated from mice induced to develop oxazolone colitis treated with CEACAM1-Fc or a control-Fc fragment. (c) Colitis scores of colon-induced oxazolone colitis treated with CEACAM1-Fc (solid bar) or a control-Fc fragment (open bar). Mice treated with CEACAM1-Fc exhibited significant reduction in colitis scores (*, P < 0.005; **, P < 0.01). V, hyper-vascularization; M, presence of mononuclear cells; H, epithelial cell hyperplasia; I, epithelial injury; G, presence of granulocytes; T, total score. (d) Th1 and Th2 cytokine production from LPLs was analyzed by ELISA of mice with oxazolone colitis treated either with CEACAM1-Fc (solid bars) or control-Fc fragment (open bars). Suppression of IFN-γ was significant (**, P < 0.01). Data are shown as mean values ± SEM from four independent experiments.
Mentions: Our results, as shown here, indicate that ligation of CEACAM1a with the CC1 mAb significantly suppresses colitis in association with inhibition of T cell production of IFN-γ by LPLs. However, these results do not define either the nature of the natural ligand for CEACAM1a in vivo and whether inhibition of Th1-mediated immunopathology can be caused by ligation of CEACAM1a with its natural ligand. To define the ligand for CEACAM1a in vivo, we examined the effects of a CEACAM1a-Fc fusion protein (sMHVR-Ig) encoding the extracellular portion of the mCEACAM1a-4L isoform that has been shown to homophilically ligate the CEACAM1a molecule in vitro (32). Therefore, mice were treated with either the CEACAM1a-Fc fusion protein or a control isotype–matched Fc fragment at a dose of 200 μg administered every other day for seven doses beginning at the time of skin sensitization in the oxazolone colitis model. Macroscopic assessment revealed that shortening of the colon was less severe in the mice treated with CEACAM1a-Fc compared with the mice administered the control-Fc fragment (Fig. 4 a). Similarly, histologic evidence of colitis was less pronounced in the CEACAM1a-Fc–treated group compared with the control-Fc–treated group (Fig. 4, b and c). These pathologic findings were associated with a significant decrease in IFN-γ production by LPLs from mice treated with the CEACAM1a-Fc fusion protein (Fig. 4 d). The fact that the decrease in immunopathologic injury observed occurred in association with suppression of IFN-γ production indicated that these were causally related.

Bottom Line: We have shown that CEACAM1 is associated with specific regulation of T helper cell (Th)1 pathways, T-bet-mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo.Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production.These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease.

View Article: PubMed Central - PubMed

Affiliation: Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

ABSTRACT
Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) is a cell surface molecule that has been proposed to negatively regulate T cell function. We have shown that CEACAM1 is associated with specific regulation of T helper cell (Th)1 pathways, T-bet-mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo. Mice treated with anti-mouse CEACAM1-specific monoclonal antibody (mAb) CC1 during the effector phase exhibited a reduced severity of trinitrobenzene sulfonic acid colitis in association with decreased interferon (IFN)-gamma production. Although oxazolone colitis has been reported as Th2 mediated, mice treated with the CC1 mAb or a CEACAM1-Fc chimeric protein exhibited a reduced severity of colitis in association with a significant reduction of IFN-gamma and T-bet activation, whereas signal transducer and activator of antigen 4 activation was unaffected. Both interleukin-4 and IFN-gamma gene-deficient mice exhibited less severe colitis induction by oxazolone. Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production. These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease.

Show MeSH
Related in: MedlinePlus