G(alpha)i2-deficient mice with colitis exhibit a local increase in memory CD4+ T cells and proinflammatory Th1-type cytokines.
Mice with targeted deletion of the G protein G(alpha)i2 develop an inflammatory bowel disease closely resembling ulcerative colitis. To better define disease pathogenesis, the mucosal immune system in G(alpha)i2-deficient mice was studied. Phenotypic analysis of large intestine lamina propria lymphocytes revealed a large increase in memory CD4+ T cells (CD44high, CD45RBlow, CD62Llow). Furthermore, expression of the mucosal homing receptor integrin beta7 was increased on mucosal, but not systemic, CD4+ T cells. Analysis of cytokine production revealed a marked increase in proinflammatory Th1-type cytokines in inflamed colons, as compared with wild-type mice or G(alpha)i2-deficient mice without colitis. Thus, IFN-gamma and IL-1beta levels were increased 13-fold and 30-fold, respectively, with more modest increases in IL-6 levels (5-fold) and TNF levels (2-fold). Inflamed colons of G(alpha)i2-deficient mice also demonstrated increased IL-12 p40 mRNA levels. No increase in IL-2, IL-4, IL-5, and IL-10 was seen. Large intestinal epithelial cells in G(alpha)i2-deficient mice with colitis were found by immunohistochemistry to express increased levels of both MHC class I and class II Ags. Colitis was associated with increased IgG levels (60-fold increase), predominantly IgG2a (135-fold increase), in large but not small intestinal secretions. This was shown by ELISPOT analysis to result from local production within the lamina propria.
Hörnquist
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CE
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Lu
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Rogers-Fani
P M
PM
Rudolph
U
U
Shappell
S
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Birnbaumer
L
L
Harriman
G R
GR
D000818:Animals; D000917:Antibody Formation; D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003093:Colitis, Ulcerative / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000502:physiology*; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D018928:Immunity, Mucosal; D007156:Immunologic Memory; D039441:Integrin alpha4; D039641:Integrin beta Chains; D016023:Integrins / Q000378:metabolism; D007420:Intestine, Large / Q000276:immunology / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
D015703:Antigens, CD; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D039641:Integrin beta Chains; D016023:Integrins; C091368:integrin beta7; D019041:L-Selectin; D039441:Integrin alpha4; D017493:Leukocyte Common Antigens; D019206:GTP-Binding Protein alpha Subunits, Gi-Go