Peroxisome proliferator-activated receptor α-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 mu M) and fenofibrate (100 mu M) significantly inhibited the cysteinyl leukottiene 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 mu M) and fenofibrate (100 mu M) did not affect the release of radioactivity from RBL-2H3 pre-incubated with [H-3]-arachidonic acid, which is considered an index of phospholipase A(2) activity. Wy-14,643 (30 mu M) and fenofibrate (100 mu M) did not directly inhibit 5-lipoxygenase activity. Troglitazone was found to directly inhibit the activity of 5-lipoxygenase. The PPAR alpha 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 mu M) and fenofibrate (100 mu M) did not induce acyl-CoA oxidase mRNA in RBL-2H3, which was reported to be induced by peroxisome proliferators via PPAR alpha in hepatocytes. Wy-14,643 (30 mu M) and fenofibrate (100 ltM) inhibited the cysteinyl leukotriene production in bone marrow-derived mast cells from PPAR alpha-null mice. It was concluded that the inhibitory effects of these peroxisome proliferators on cysteinyl leukotriene production are independent of PPAR alpha in mast cells. (c) 2006 Elsevier B.V. All rights reserved.