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* Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97239;
Department of Neurology, Oregon Health and Science University, Portland, OR 97239;
Departments of Medicine and Pathology, University of Vermont, Burlington, VT 05405;
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239; and
¶ Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239
Females tend to have stronger Th1-mediated immune responses and are more prone to develop autoimmune diseases, including multiple sclerosis. Macrophages are major effector cells capable of mediating or modulating immune responses in experimental autoimmune encephalomyelitis (EAE). IL-13 and estrogen have opposing roles on macrophages (the former enhancing and the latter inhibiting) in terms of MHC class II (MHC II) up-regulation and, thus, these factors might influence susceptibility to EAE differently in females vs males. In accordance with this hypothesis, females lacking IL-13 displayed lower incidence and milder EAE disease severity than males after immunization with myelin oligodendrocyte glycoprotein (MOG)-35–55 peptide/CFA/pertussis toxin. Female IL-13 knockout (KO) mice with EAE consistently had reduced infiltration of CD11b+ macrophages in the CNS along with significantly reduced expression of MHC II on these cells. Impaired MHC II expression was further corroborated upon LPS stimulation of female but not male bone marrow-derived CD11b+ macrophages from IL-13KO mice, with restored expression after IL-13 pretreatment of female but not male macrophages. APCs from IL-13KO females induced less proliferation by MOG-35–55-reactive T cells, and splenocytes from MOG peptide-immunized females had lower expression of IL-12, IFN-
, MIP-2, and IFN--inducible protein 10 than males. In contrast, these splenocytes had higher expression of anti-inflammatory factors, IL-10, TGF-β1, and FoxP3, a cytokine pattern typical of regulatory type II monocytes. These data suggest that the difference in EAE susceptibility in females is strongly influenced by gender-specific proinflammatory effects of IL-13, mediated in part through up-regulation of Th1-inducing cytokines and MHC II on CD11b+ macrophages.
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1 This work was supported by National Institutes of Health Grants NS045445, NS049210, NS023221, AI041747, AI058052, AI045666, NS036526, and AI051454, National Multiple Sclerosis Society Grants RG3405-B-5 and RG3794-A-4, the Nancy Davis Center Without Walls, and the Biomedical Laboratory R&D Service, Department of Veterans Affairs.
2 Address correspondence and reprint requests to Dr. Halina Offner, Neuroimmunology Research R&D-31, Portland Veterans Affairs Medical Center, 3710 S.W. U.S. Veterans Hospital Road, Portland, OR 97239. E-mail address: offnerva{at}ohsu.edu
3 Abbreviations used in this paper: MS, multiple sclerosis; MHC II, MHC class II; EAE, experimental autoimmune encephalomyelitis; KO, knockout; WT, wild type; MOG, myelin oligodendrocyte glycoprotein; Ptx, pertussis toxin; CDI, cumulative disease index; RT, room temperature; LN, lymph node; IP-10, IFN--inducible protein 10; BMDM, bone marrow-derived macrophage.
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