p38 mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes

p38 mitogen-activated protein kinase (MAPK) is activated by inflammatory st imuli such as bacterial lipopolysaccharide (LPS), interleukin-1, and tumor necrosis factor. We have previously shown that the pyridinyl imidazole SE 2 03580, which inhibits it, blocks the interleukin-1 induction of cyclooxygen ase-2 (COX-2) and matrix metalloproteinase 1 and 3 mRNAs in fibroblasts. He re we explore the role of p38 MAPK in the response of human monocytes to LP S, 0.1 mu M SB 203580 significantly inhibited the LPS induction of COX-2 an d tumor necrosis factor protein and mRNAs. The activity of MAPK-activated p rotein kinase-2 (a substrate of p38 MAPK) in the cells was commensurately r educed. Some isoforms of c-jun N-terminal kinase (which is also activated b y LPS) are sensitive to SE 203580; the inhibitor had little effect on monoc yte c-jun N-terminal kinases up to 2 mu m We investigated the mechanism of inhibition of COX-2 induction. Transcription (measured by a nuclear run-on assay) was 60% inhibited by SE 203580 (2 mu M.), Importantly, we found that p38 MAPK was essential for stabilizing COX-2 mRNA: when cells stimulated f or 4 h with LPS were treated with actinomycin D, COX-2 mRNA decayed slowly. Treatment of stimulated cells with 2 mu M SE 203580 caused a rapid disappe arance of COX-2 mRNA, even with actinomycin D present. We conclude p38 MAPK plays a role in the transcription and stabilization of COX-2 mRNA.