SB202190, A SELECTIVE INHIBITOR OF P38 MITOGEN-ACTIVATED PROTEIN-KINASE, IS A POWERFUL REGULATOR OF LPS-INDUCED MESSENGER-RNAS IN MONOCYTES

Inhibitors of p38 mitogen-activated protein kinase (p38) have been rep orted to block tumor necrosis factor alpha (TNF-alpha) and interleukin -1 beta (IL-1 beta) production iu monocytes at the level of mRNA trans lation, Yea, several studies document that p38 can phosphorylate and a ctivate specific transcription factors. Thus, to understand better the role of p38 during monocyte activation, we sought to determine the ex tent to which p38 is required for lipopolysaccharide (LPS)-induced gen e expression. For this, differential mRNA display was used to identify LPS-induced genes whose expression was blocked by SB202190, a specifi c inhibitor of p38, A partial screen identified 10 genes in monoyctes induced 4- to 74-fold by LPS, Of these, genes encoding interferon-indu ced gene 15, neuroleukin, radiation-inducible immediate-early gene-1, A20, IL-1 beta, and superoxide dismutase were suppressed >50% by SB202 190, LPS-induced gene activation was not blocked by cycloheximide, ind icating that synthesis of intermediate proteins was not required, SB20 2190 blocked gene induction by 50% when present between 41 and 123 nM, consistent with the potency of this compound as a p38 inhibitor, Furt hermore, the ability of SB202190 to block gene activation was stimulus -dependent. LPS and interferon-alpha (IFN-alpha) both up-regulated neu roleukin mRNA, but only LPS-induced neuroleukin mRNA was suppressed by SB202190, In contrast, TNF-alpha and LPS both induced IL-8 mRNA, and induction by either TNF-alpha or LPS was blocked by SB202190. These da ta were consistent with the ability of LPS and TNF-alpha, but not IFN- alpha, to activate p38 in monocytes, The results provide pharmacologic al evidence that p38 may be a key mediator of inducible gene expressio n in monocytes, but its role is stimulus and gene specific.