A selective role for the TNF p55 receptor in autocrine signaling following IFN-gamma stimulation in experimental autoimmune uveoretinitis.
IFN-gamma stimulates macrophage activation and NO production, which leads to destruction of the retina in experimental autoimmune uveoretinitis. In this study, we investigate the mechanism of disease resistance in TNF p55 receptor-deficient animals. We show that although T cell priming is relatively unaffected, macrophages lacking the TNF p55 receptor fail to produce NO following IFN-gamma stimulation because of a requirement for autocrine TNF-alpha signaling through the TNF p55 receptor. In contrast to the impaired activation of NO synthesis, MHC class II up-regulation was indistinguishable in wild-type and TNFRp55-/- mice stimulated with IFN-gamma. These defects could be overcome by stimulating macrophages with LPS. Together, these results show that selected aspects of IFN-gamma activation are controlled by autocrine secretion of TNF-alpha, but that this control is lost in the presence of signals generated by pathogen-associated molecular patterns recognizing receptors.
Calder
Claudia J
CJ
Department of Pathology and Microbiology, University of Bristol, Bristol, United Kingdom.
Nicholson
Lindsay B
LB
Dick
Andrew D
AD
D000818:Animals; D019898:Autocrine Communication; D001327:Autoimmune Diseases / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000276:immunology; D011994:Recombinant Proteins; D012173:Retinitis / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014605:Uveitis / Q000276:immunology*
D019013:CD40 Antigens; D000949:Histocompatibility Antigens Class II; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D007371:Interferon-gamma