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Evaluation of the Effects of 17ß-Estradiol (17ß-E2) on Gene Expression in Experimental Autoimmune Encephalomyelitis Using DNA Microarray

Department of Neurology, Oregon Health Sciences University (A.M., A.A.V., H.O.), Portland, Oregon 97201; L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (A.M.), 53-114 Wroclaw, Poland; Neuroimmunology Research, Veterans Affairs Medical Center (A.M., J.D., A.Z., A.A.V., H.O.), Portland, Oregon 97201; and Department of Molecular Microbiology and Immunology, Oregon Health Sciences University (A.A.V.), Portland, Oregon 97201

Address all correspondence and requests for reprints to: Dr. Agata Matejuk, R&D-31, Veterans Affairs Medical Center, 3710 SW U.S. Veterans Hospital Road, Portland, Oregon 97201. E-mail: matejuka{at}ohsu.edu

The aim of this study was to identify immune-related genes affected by treatment with 17ß-estradiol (17ß-E2) that contribute to protection of T cell antigen receptor double transgenic mice from experimental autoimmune encephalomyelitis (EAE). The Affymetrix microarray system was used to screen more than 12,000 genes from E2-treated mice protected from EAE vs. control mice with severe EAE. In general, E2 treatment affected about 10% of the genes tested, but only 18 cytokine, chemokine/receptor, adhesion molecule, or activation genes were up- or down-regulated more than 2.4-fold by E2 treatment. Down-regulated genes included TNF (an important proinflammatory cytokine in EAE); peptidoglycan recognition proteins (Pgrp); regulated on activation, normal T cell expressed and secreted (RANTES); and neural cell adhesion molecule (MCP-1). Up-regulated genes included cytotoxic T lymphocyte antigen-4 (CTLA-4; known to inhibit T cell activation), TGFß3, IL-18, and two interferon--induced genes, the chemokines: monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1ß (MIP-1ß), vascular cell adhesion molecule (VCAM), and disintegrin metalloprotease (thought to regulate TNF production). These results implicate a limited set of known and previously unsuspected E2-sensitive genes that may be crucial for inhibition of EAE and potentially the human disease, multiple sclerosis.

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