Peroxisome proliferator-activated receptor alpha-independent effects of peroxisome proliferators on cysteinyl leukotriene production in mast cells.
The effects of peroxisome proliferators, the ligands of a nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha, on cysteinyl leukotriene production were investigated in rodent mast cells. Peroxisome proliferators Wy-14,643 (30 microM) and fenofibrate (100 microM) significantly inhibited the cysteinyl leukotriene production that was induced by antigen (Ag) treatment after overnight sensitization to Ag specific immunoglobulin E (IgE) in a rat basophilic leukemia (RBL)-2H3 mast cell line. Similar inhibition by these drugs was observed in IgE and Ag-treated mouse bone marrow-derived mast cells, A23187-treated RBL-2H3 and A23187-treated mouse peritoneal macrophages. Wy-14,643 (30 microM) and fenofibrate (100 microM) did not affect the release of radioactivity from RBL-2H3 pre-incubated with [(3)H]-arachidonic acid, which is considered an index of phospholipase A(2) activity. Wy-14,643 (30 microM) and fenofibrate (100 microM) did not directly inhibit 5-lipoxygenase activity. Troglitazone was found to directly inhibit the activity of 5-lipoxygenase. The PPARalpha mRNA level was at less than the limit of detection for the realtime polymerase chain reaction both in RBL-2H3 and bone marrow-derived mast cells. Wy-14,643 (30 microM) and fenofibrate (100 microM) did not induce acyl-CoA oxidase mRNA in RBL-2H3, which was reported to be induced by peroxisome proliferators via PPARalpha in hepatocytes. Wy-14,643 (30 microM) and fenofibrate (100 microM) inhibited the cysteinyl leukotriene production in bone marrow-derived mast cells from PPARalpha-null mice. It was concluded that the inhibitory effects of these peroxisome proliferators on cysteinyl leukotriene production are independent of PPARalpha in mast cells.
Yamashita
Masamichi
M
Department of Pathophysiology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan. may@tohoku-pharm.ac.jp
D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003545:Cysteine / Q000096:biosynthesis*; D011345:Fenofibrate / Q000494:pharmacology*; D006596:Hexosaminidases / Q000378:metabolism; D007073:Immunoglobulin E / Q000378:metabolism; D015289:Leukotrienes / Q000096:biosynthesis*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology*; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D010741:Phospholipases A / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats
D015289:Leukotrienes; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; C112381:cysteinyl-leukotriene; D007073:Immunoglobulin E; C006253:pirinixic acid; D001094:Arachidonate 5-Lipoxygenase; D042962:Acyl-CoA Oxidase; D010741:Phospholipases A; D006596:Hexosaminidases; D003545:Cysteine; D011345:Fenofibrate