Liver X receptor agonist regulation of Th17  lymphocyte function in autoimmunity.
CD4+ Th17 cells are believed to play an important role in the development of a variety of autoimmune diseases including EAE, an animal model of MS. Previously, we and others demonstrated that LXR agonists suppressed the activation of primary glial cells and blocked the development of EAE. The present studies demonstrated that the LXR agonist T0901317 suppressed IL-17A expression from splenocytes derived from Valpha2.3/Vbeta8.2 TCR transgenic mice and from MOG(35-55)-immunized C57BL/6 mice. Furthermore, in vitro treatment with IL-23 alone or in combination with MOG(35-55) induced IL-17A expression from splenocytes derived from MOG(35-55)-immunized mice, and T0901317 blocked this induction. In vitro treatment with the LXR agonist suppressed IL-23R expression by splenocytes. In addition, in vivo treatment with the LXR agonist suppressed IL-17A and IL-23R mRNA and protein expression in EAE mice. These studies suggest that LXR agonists suppress EAE, at least in part by suppressing IL-23 signaling. Recent studies indicate that the cytokines IL-21 and IL-22 are produced by Th17 cells and modulate immune responses. Our studies demonstrate that the LXR agonist T0901317 suppressed MOG(35-55)-induced expression of IL-21 and IL-22 mRNA in splenocytes derived from MOG(35-55)-immunized mice. Finally, we demonstrate that the LXR agonist T0901317 suppressed the development of EAE in an experimental paradigm involving treatment of established EAE. Collectively, these studies suggest that LXR agonists may be effective in the treatment of MS.
Xu
Jihong
J
Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Wagoner
Gail
G
Douglas
James C
JC
Drew
Paul D
PD
D000818:Animals; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism / Q000494:pharmacology; D007378:Interleukins / Q000235:genetics; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D018123:Receptors, Interleukin / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000097043:Interleukin-22; D000098546:Interleukin-21; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D000071518:Liver X Receptors; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018123:Receptors, Interleukin; D013449:Sulfonamides; D000097043:Interleukin-22; D000098546:Interleukin-21; C571327:Mog protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C528688:interleukin-23 receptor, mouse