p38 Mitogen-activated Protein Kinase Regulates Cyclooxygenase-2 mRNA Stability and Transcription in Lipopolysaccharide-treated Human Monocytes

• DOI: 10.1074/jbc.274.1.264
• Publication Date: 2002-07-26T15:00:08Z
• Authors: Jonathan L.E. Dean; Matthew Brook; Andrew R. Clark; Jeremy Saklatvala
• Keywords: Lipopolysaccharides; 0301 basic medicine; Transcription, Genetic; Pyridines; Tumor Necrosis Factor-alpha; Imidazoles; JNK Mitogen-Activated Protein Kinases; Membrane Proteins; p38 Mitogen-Activated Protein Kinases; Monocytes; Isoenzymes; 03 medical and health sciences; Cyclooxygenase 2; Prostaglandin-Endoperoxide Synthases; Calcium-Calmodulin-Dependent Protein Kinases; Humans; RNA, Messenger; Enzyme Inhibitors; Mitogen-Activated Protein Kinases

p38 mitogen-activated protein kinase (MAPK) is activated by inflammatory stimuli such as bacterial lipopolysaccharide (LPS), interleukin-1, and tumor necrosis factor. We have previously shown that the pyridinyl imidazole SB 203580, which inhibits it, blocks the interleukin-1 induction of cyclooxygenase-2 (COX-2) and matrix metalloproteinase 1 and 3 mRNAs in fibroblasts. Here we explore the role of p38 MAPK in the response of human monocytes to LPS. 0.1 microM SB 203580 significantly inhibited the LPS induction of COX-2 and tumor necrosis factor protein and mRNAs. The activity of MAPK-activated protein kinase-2 (a substrate of p38 MAPK) in the cells was commensurately reduced. Some isoforms of c-jun N-terminal kinase (which is also activated by LPS) are sensitive to SB 203580; the inhibitor had little effect on monocyte c-jun N-terminal kinases up to 2 microM. We investigated the mechanism of inhibition of COX-2 induction. Transcription (measured by a nuclear run-on assay) was 60% inhibited by SB 203580 (2 microM). Importantly, we found that p38 MAPK was essential for stabilizing COX-2 mRNA: when cells stimulated for 4 h with LPS were treated with actinomycin D, COX-2 mRNA decayed slowly. Treatment of stimulated cells with 2 microM SB 203580 caused a rapid disappearance 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.