Peroxisome proliferator-activated receptor alpha agonists as therapy for autoimmune disease.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPAR gamma ligands, which include the naturally occurring PG metabolite 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), as well as thiazolidinediones, have been shown to have anti-inflammatory activity. The PPAR alpha agonists, gemfibrozil, ciprofibrate, and fenofibrate, have an excellent track history as oral agents used to treat hypertriglyceridemia. In the present study, we demonstrate that these PPAR alpha agonists can increase the production of the Th2 cytokine, IL-4, and suppress proliferation by TCR transgenic T cells specific for the myelin basic protein Ac1-11, as well as reduce NO production by microglia. Oral administration of gemfibrozil and fenofibrate inhibited clinical signs of experimental autoimmune encephalomyelitis. More importantly, gemfibrozil was shown to shift the cytokine secretion of human T cell lines by inhibiting IFN-gamma and promoting IL-4 secretion. These results suggest that PPAR alpha agonists such as gemfibrozil and fenofibrate, may be attractive candidates for use in human inflammatory conditions such as multiple sclerosis.
Lovett-Racke
Amy E
AE
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Hussain
Rehana Z
RZ
Northrop
Sara
S
Choy
Judy
J
Rocchini
Anne
A
Matthes
Lela
L
Chavis
Janet A
JA
Diab
Asim
A
Drew
Paul D
PD
Racke
Michael K
MK
D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011345:Fenofibrate / Q000008:administration & dosage / Q000494:pharmacology; D015248:Gemfibrozil / Q000008:administration & dosage / Q000494:pharmacology; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008830:Microbodies / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists*
D016207:Cytokines; D006131:Growth Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D009569:Nitric Oxide; D015248:Gemfibrozil; D011345:Fenofibrate