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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 CC1 mAb injection on the induction of TNBS colitis and cytokine production. (a) Body weight of mice subjected to TNBS colitis treated either with control IgG1 mAb (□), with CC1 mAb before skin painting and before rectal challenge twice (▪), before skin painting (•), or before rectal challenge (○) in C57BL/6 mice are shown. One group was injected with 50% ethanol (▴) instead of TNBS. Data are shown as mean values ± SEM and represent eight mice per group. (b) Macroscopic pictures of colons from mice induced with TNBS colitis treated with or without CC1 mAb are shown. (c) Hematoxylin and eosin–stained pictures from TNBS colitis treated with or without CC1 mAb are shown (×100). One representative picture from each group of eight is shown. A, control mAb; B, CC1 mAb administered twice; C, CC1 mAb administered before skin painting; D, CC1 mAb administered before rectal challenge. (d) Quantitative histopathologic assessment of TNBS colitis activity shows a significant (*, P < 0.05 by t test) suppression in mice treated with CC1 mAb either twice or before rectal challenge when compared with the control mAb–treated group. Samples were collected from mice with TNBS colitis treated either with control mAb (solid bar) or CC1 mAb twice (open bar) before skin painting (shaded bar) or before rectal challenge (striped bar). Data are shown as mean values ± SEM and represent eight mice per group. (e) Th1 and Th2 cytokine production from LPLs was analyzed by ELISA. Samples were collected from mice with TNBS colitis treated either with control mAb (solid bars) or CC1 mAb twice (open bars) before skin painting (shaded bars) or before rectal challenge (striped bars). One group of mice was administered ethanol without TNBS for the skin sensitization and rectal challenge (hatched bars). CC1 mAb–treated group treated either twice or before rectal challenge exhibited significant suppression of IFN-γ production when compared with the control mAb–treated group (**, P < 0.01). Data are shown as mean values ± SEM and represent pooled values from eight independent experiments.
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fig1: Effect of CC1 mAb injection on the induction of TNBS colitis and cytokine production. (a) Body weight of mice subjected to TNBS colitis treated either with control IgG1 mAb (□), with CC1 mAb before skin painting and before rectal challenge twice (▪), before skin painting (•), or before rectal challenge (○) in C57BL/6 mice are shown. One group was injected with 50% ethanol (▴) instead of TNBS. Data are shown as mean values ± SEM and represent eight mice per group. (b) Macroscopic pictures of colons from mice induced with TNBS colitis treated with or without CC1 mAb are shown. (c) Hematoxylin and eosin–stained pictures from TNBS colitis treated with or without CC1 mAb are shown (×100). One representative picture from each group of eight is shown. A, control mAb; B, CC1 mAb administered twice; C, CC1 mAb administered before skin painting; D, CC1 mAb administered before rectal challenge. (d) Quantitative histopathologic assessment of TNBS colitis activity shows a significant (*, P < 0.05 by t test) suppression in mice treated with CC1 mAb either twice or before rectal challenge when compared with the control mAb–treated group. Samples were collected from mice with TNBS colitis treated either with control mAb (solid bar) or CC1 mAb twice (open bar) before skin painting (shaded bar) or before rectal challenge (striped bar). Data are shown as mean values ± SEM and represent eight mice per group. (e) Th1 and Th2 cytokine production from LPLs was analyzed by ELISA. Samples were collected from mice with TNBS colitis treated either with control mAb (solid bars) or CC1 mAb twice (open bars) before skin painting (shaded bars) or before rectal challenge (striped bars). One group of mice was administered ethanol without TNBS for the skin sensitization and rectal challenge (hatched bars). CC1 mAb–treated group treated either twice or before rectal challenge exhibited significant suppression of IFN-γ production when compared with the control mAb–treated group (**, P < 0.01). Data are shown as mean values ± SEM and represent pooled values from eight independent experiments.

Mentions: CEACAM1 is known to be expressed constitutively by murine and human DCs and to be an early activation antigen on human and mouse T cells that may persist for up to 1 wk after activation (3, 18–22). However, little is known about ligation of CEACAM1 on these cell types in vivo. Therefore, we assessed whether ligation of CEACAM1 with an anti-CEACAM1–specific mAb CC1, which is directed against the NH2-terminal domain of CEACAM1a, affected the course of TNBS colitis, a model mediated primarily by Th1 cytokines in certain strains of mice (23). To test whether CEACAM1a is involved in T cell–mediated colonic inflammation at the time of T cell priming by DCs or at the time of the effector response by intestinal T cells, we assessed the effects of CC1 mAb at the time of either T cell priming (before skin painting) and/or the effector phase (before rectal challenge) in the TNBS colitis model. Animals that received TNBS in association with either a control mAb (Fig. 1 a, □) or the CC1 mAb before skin painting (Fig. 1 a, •) experienced severe weight loss. In contrast, mice that received the CC1 mAb either before rectal challenge (Fig. 1 a, ○) or both skin painting and rectal challenge twice (Fig. 1 a, ▪) experienced less weight loss. This was directly reflected in the levels of macroscopic injury observed in that mice treated with the CC1 mAb either before rectal challenge or twice did not exhibit significant shortening and thickening of the colon (Fig. 1 b). Consistent with these macroscopic changes, the control mAb–treated group and groups receiving the CC1 mAb only before skin painting exhibited marked, transmural infiltration with inflammatory cells and injury with ulceration (Fig. 1 c, A and C, respectively). In contrast, mice treated with the CC1 mAb either twice or before rectal challenge exhibited less severe histologic features of colitis (Fig. 1 c, B and D, respectively). When quantified by a histologic scoring system for evidence of inflammation and injury, these histologic challenges were highly significant (Fig. 1 d).


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 CC1 mAb injection on the induction of TNBS colitis and cytokine production. (a) Body weight of mice subjected to TNBS colitis treated either with control IgG1 mAb (□), with CC1 mAb before skin painting and before rectal challenge twice (▪), before skin painting (•), or before rectal challenge (○) in C57BL/6 mice are shown. One group was injected with 50% ethanol (▴) instead of TNBS. Data are shown as mean values ± SEM and represent eight mice per group. (b) Macroscopic pictures of colons from mice induced with TNBS colitis treated with or without CC1 mAb are shown. (c) Hematoxylin and eosin–stained pictures from TNBS colitis treated with or without CC1 mAb are shown (×100). One representative picture from each group of eight is shown. A, control mAb; B, CC1 mAb administered twice; C, CC1 mAb administered before skin painting; D, CC1 mAb administered before rectal challenge. (d) Quantitative histopathologic assessment of TNBS colitis activity shows a significant (*, P < 0.05 by t test) suppression in mice treated with CC1 mAb either twice or before rectal challenge when compared with the control mAb–treated group. Samples were collected from mice with TNBS colitis treated either with control mAb (solid bar) or CC1 mAb twice (open bar) before skin painting (shaded bar) or before rectal challenge (striped bar). Data are shown as mean values ± SEM and represent eight mice per group. (e) Th1 and Th2 cytokine production from LPLs was analyzed by ELISA. Samples were collected from mice with TNBS colitis treated either with control mAb (solid bars) or CC1 mAb twice (open bars) before skin painting (shaded bars) or before rectal challenge (striped bars). One group of mice was administered ethanol without TNBS for the skin sensitization and rectal challenge (hatched bars). CC1 mAb–treated group treated either twice or before rectal challenge exhibited significant suppression of IFN-γ production when compared with the control mAb–treated group (**, P < 0.01). Data are shown as mean values ± SEM and represent pooled values from eight independent experiments.
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Related In: Results  -  Collection

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fig1: Effect of CC1 mAb injection on the induction of TNBS colitis and cytokine production. (a) Body weight of mice subjected to TNBS colitis treated either with control IgG1 mAb (□), with CC1 mAb before skin painting and before rectal challenge twice (▪), before skin painting (•), or before rectal challenge (○) in C57BL/6 mice are shown. One group was injected with 50% ethanol (▴) instead of TNBS. Data are shown as mean values ± SEM and represent eight mice per group. (b) Macroscopic pictures of colons from mice induced with TNBS colitis treated with or without CC1 mAb are shown. (c) Hematoxylin and eosin–stained pictures from TNBS colitis treated with or without CC1 mAb are shown (×100). One representative picture from each group of eight is shown. A, control mAb; B, CC1 mAb administered twice; C, CC1 mAb administered before skin painting; D, CC1 mAb administered before rectal challenge. (d) Quantitative histopathologic assessment of TNBS colitis activity shows a significant (*, P < 0.05 by t test) suppression in mice treated with CC1 mAb either twice or before rectal challenge when compared with the control mAb–treated group. Samples were collected from mice with TNBS colitis treated either with control mAb (solid bar) or CC1 mAb twice (open bar) before skin painting (shaded bar) or before rectal challenge (striped bar). Data are shown as mean values ± SEM and represent eight mice per group. (e) Th1 and Th2 cytokine production from LPLs was analyzed by ELISA. Samples were collected from mice with TNBS colitis treated either with control mAb (solid bars) or CC1 mAb twice (open bars) before skin painting (shaded bars) or before rectal challenge (striped bars). One group of mice was administered ethanol without TNBS for the skin sensitization and rectal challenge (hatched bars). CC1 mAb–treated group treated either twice or before rectal challenge exhibited significant suppression of IFN-γ production when compared with the control mAb–treated group (**, P < 0.01). Data are shown as mean values ± SEM and represent pooled values from eight independent experiments.
Mentions: CEACAM1 is known to be expressed constitutively by murine and human DCs and to be an early activation antigen on human and mouse T cells that may persist for up to 1 wk after activation (3, 18–22). However, little is known about ligation of CEACAM1 on these cell types in vivo. Therefore, we assessed whether ligation of CEACAM1 with an anti-CEACAM1–specific mAb CC1, which is directed against the NH2-terminal domain of CEACAM1a, affected the course of TNBS colitis, a model mediated primarily by Th1 cytokines in certain strains of mice (23). To test whether CEACAM1a is involved in T cell–mediated colonic inflammation at the time of T cell priming by DCs or at the time of the effector response by intestinal T cells, we assessed the effects of CC1 mAb at the time of either T cell priming (before skin painting) and/or the effector phase (before rectal challenge) in the TNBS colitis model. Animals that received TNBS in association with either a control mAb (Fig. 1 a, □) or the CC1 mAb before skin painting (Fig. 1 a, •) experienced severe weight loss. In contrast, mice that received the CC1 mAb either before rectal challenge (Fig. 1 a, ○) or both skin painting and rectal challenge twice (Fig. 1 a, ▪) experienced less weight loss. This was directly reflected in the levels of macroscopic injury observed in that mice treated with the CC1 mAb either before rectal challenge or twice did not exhibit significant shortening and thickening of the colon (Fig. 1 b). Consistent with these macroscopic changes, the control mAb–treated group and groups receiving the CC1 mAb only before skin painting exhibited marked, transmural infiltration with inflammatory cells and injury with ulceration (Fig. 1 c, A and C, respectively). In contrast, mice treated with the CC1 mAb either twice or before rectal challenge exhibited less severe histologic features of colitis (Fig. 1 c, B and D, respectively). When quantified by a histologic scoring system for evidence of inflammation and injury, these histologic challenges were highly significant (Fig. 1 d).

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