Peroxisome proliferator-activated receptor α agonists as therapy for autoimmune disease

被引:186
作者
Lovett-Racke, AE
Hussain, RZ
Northrop, S
Choy, J
Rocchini, A
Matthes, L
Chavis, JA
Diab, A
Drew, PD
Racke, MK
机构
[1] Univ Texas, SW Med Ctr, Dept Neurol, Dallas, TX 75390 USA
[2] Univ Texas, SW Med Ctr, Ctr Immunol, Dallas, TX 75390 USA
[3] Univ Arkansas Med Sci, Dept Neurobiol & Dev Sci, Little Rock, AR 72205 USA
关键词
D O I
10.4049/jimmunol.172.9.5790
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPARgamma 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 PPARalpha 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 PPARa 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 PPARa agonists such as gemfibrozil and fenofibrate, may be attractive candidates for use in human inflammatory conditions such as multiple sclerosis.
引用
收藏
页码:5790 / 5798
页数:9
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共 43 条
  • [21] KENNEDY MK, 1992, J IMMUNOL, V149, P2496
  • [22] Ectopic expression of activated Stat6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells
    Kurata, H
    Lee, HJ
    O'Garra, A
    Arai, N
    [J]. IMMUNITY, 1999, 11 (06) : 677 - 688
  • [23] Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs
    Lehmann, JM
    Lenhard, JM
    Oliver, BB
    Ringold, GM
    Kliewer, SA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (06) : 3406 - 3410
  • [24] Peroxisome proliferator-activate inhibit development of atherosclerosis in LDL receptor-deficient mice
    Li, AC
    Brown, KK
    Silvestre, MJ
    Willson, TM
    Palinski, W
    Glass, CK
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2000, 106 (04) : 523 - 531
  • [25] Longitudinal study of myelin basic protein-specific T-cell receptors during the course of multiple sclerosis
    LovettRacke, AE
    Martin, R
    McFarland, HF
    Racke, MK
    Utz, U
    [J]. JOURNAL OF NEUROIMMUNOLOGY, 1997, 78 (1-2) : 162 - 171
  • [26] Microstructural design criteria of fully lamellar TiAl alloys for improved creep strength
    Maruyama, K
    Yamamoto, R
    Wegmann, G
    [J]. JOURNAL DE PHYSIQUE IV, 2000, 10 (P6): : 9 - 14
  • [27] Peroxisome proliferator-activated receptor-γ activators inhibit IFN-γ-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells
    Marx, N
    Mach, F
    Sauty, A
    Leung, JH
    Sarafi, MN
    Ransohoff, RM
    Libby, P
    Plutzky, J
    Luster, AD
    [J]. JOURNAL OF IMMUNOLOGY, 2000, 164 (12) : 6503 - 6508
  • [28] PPAR activators as antiinflammatory mediators in human T lymphocytes -: Implications for atherosclerosis and transplantation-associated arteriosclerosis
    Marx, N
    Kehrle, B
    Kohlhammer, K
    Grüb, M
    Koenig, W
    Hombach, V
    Libby, P
    Plutzky, J
    [J]. CIRCULATION RESEARCH, 2002, 90 (06) : 703 - 710
  • [29] Peroxisome proliferator-activated receptor-gamma agonists inhibit experimental allergic encephalomyelitis by blocking IL-12 production, IL-12 signaling and Th1 differentiation
    Natarajan, C
    Bright, JJ
    [J]. GENES AND IMMUNITY, 2002, 3 (02) : 59 - 70
  • [30] Amelioration of experimental autoimmune encephalomyelitis in C57BL/6 mice by an agonist of peroxisome proliferator-activated receptor-γ
    Niino, M
    Iwabuchi, K
    Kikuchi, S
    Ato, M
    Morohashi, T
    Ogata, A
    Tashiro, K
    Onoé, K
    [J]. JOURNAL OF NEUROIMMUNOLOGY, 2001, 116 (01) : 40 - 48