title: IFN-gamma shapes immune invasion of the central nervous system via regulation of chemokines.
abstract: Dynamic interplay between cytokines and chemokines directs trafficking of leukocyte subpopulations to tissues in autoimmune inflammation. We have examined the role of IFN-gamma in directing chemokine production and leukocyte infiltration to the CNS in experimental autoimmune encephalomyelitis (EAE). BALB/c and C57BL/6 mice are resistant to induction of EAE by immunization with myelin basic protein. However, IFN-gamma-deficient (BALB/c) and IFN-gammaR-deficient (C57BL/6) mice developed rapidly progressing lethal disease. Widespread demyelination and disseminated leukocytic infiltration of spinal cord were seen, unlike the focal perivascular infiltrates in SJL/J mice. Gr-1+ neutrophils predominated in CNS, and CD4+ T cells with an activated (CD69+, CD25+) phenotype and eosinophils were also present. RANTES and macrophage chemoattractant protein-1, normally up-regulated in EAE, were undetectable in IFN-gamma- and IFN-gammaR-deficient mice. Macrophage inflammatory protein-2 and T cell activation gene-3, both neutrophil-attracting chemokines, were strongly up-regulated. There was no induction of the Th2 cytokines, IL-4, IL-10, or IL-13. RNase protection assays and RT-PCR showed the prevalence of IL-2, IL-3, and IL-15, but no increase in IL-12p40 mRNA levels in IFN-gamma- or IFN-gammaR-deficient mice with EAE. Lymph node cells from IFN-gamma-deficient mice proliferated in response to myelin basic protein, whereas BALB/c lymph node cells did not. These findings show a regulatory role for IFN-gamma in EAE, acting on T cell proliferation and directing chemokine production, with profound implications for the onset and progression of disease.
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, and Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: E H
authors.initials: EH
authors.lastname: Tran
authors.forename: E N
authors.initials: EN
authors.lastname: Prince
authors.forename: T
authors.initials: T
authors.lastname: Owens
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002417:Cattle; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D054402:Chemokine CCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019742:Chemokines, CC; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000276:immunology; D009186:Myelin Sheath / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D054401:Receptors, CCR8; D017471:Receptors, Interferon / Q000235:genetics; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D054402:Chemokine CCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D007371:Interferon-gamma; D004676:Myelin Basic Protein; D012333:RNA, Messenger; D054401:Receptors, CCR8; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C065971:CCL1 protein, human; C489319:Ccr8 protein, mouse; C404915:Cxcl2 protein, mouse