Published online before print June 3, 2004
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Critical Care Medicine Department, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland
3Correspondence: Critical Care Medicine Department, Bldg. 10, Rm. 7D43, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892. E-mail: rdanner{at}nih.gov
Nitric oxide (NO·) contributes to vascular collapse in septic shock and regulates inflammation. Here, we demonstrate in lipopolysaccharide (LPS)-stimulated human THP-1 cells and monocytes that NO· regulates interleukin (IL)-8 and tumor necrosis factor 
(TNF-) by distinct mechanisms. Dibutyryl-cyclic guanosine 5'-monophosphate (cGMP) failed to simulate NO·-induced increases in TNF- or IL-8 production. In contrast, dibutyryl-cyclic adenosine monophosphate blocked NO·-induced production of TNF- (P=0.009) but not IL-8. NO· increased IL-8 (5.7-fold at 4 h; P=0.04) and TNF- mRNA levels (2.2-fold at 4 h; P=0.037). However, nuclear run-on assays demonstrated that IL-8 transcription was slightly decreased by NO· (P=0.08), and TNF- was increased (P=0.012). Likewise, NO· had no effect on IL-8 promoter activity (P=0.84) as measured by reporter gene assay. In THP-1 cells and human primary monocytes treated with actinomycin D, NO· had no effect on TNF- mRNA stability (P>0.3 for both cell types) but significantly stabilized IL-8 mRNA (P=0.001 for both cell types). Because of its role in mRNA stabilization, the p38 mitogen-activated protein kinase (MAPK) pathway was examined and found to be activated by NO· in LPS-treated THP-1 cells and human monocytes. Further, SB202190, a p38 MAPK inhibitor, was shown to block NO·-induced stabilization of IL-8 mRNA (P<0.02 for both cell types). Thus, NO· regulates IL-8 but not TNF- post-transcriptionally. IL-8 mRNA stabilization by NO· is independent of cGMP and at least partially dependent on p38 MAPK activation.
Key Words: cytokines • protein kinases • gene regulation • mRNA • cAMP • cGMP
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