ACTIONS OF IL-1 ARE SELECTIVELY CONTROLLED BY P38 MITOGEN-ACTIVATED PROTEIN-KINASE - REGULATION OF PROSTAGLANDIN-H SYNTHASE-2, METALLOPROTEINASES, AND IL-6 AT DIFFERENT LEVELS

The role of p38 mitogen-activated protein kinase (MAPK) in responses o f human fibroblasts and vascular endothelial cells to IL-1 was investi gated by use of a pyridinyl imidazole compound (SE 203580), which spec ifically inhibits the enzyme. SB 203580 inhibited (50% inhibitory conc entration similar to 0.5 mu M) IL-1-induced phosphorylation of heat sh ock protein 27 (an indicator of p38 MAPK activity) in fibroblasts with out affecting the other known IL-1-activated protein kinase pathways ( p42/p44 MAPK, p54 MAPK/c-Jun N-terminal kinase and beta-casein kinase) . SB 203580 significantly inhibited IL-1-stimulated IL-6, (30 to 50% a t 1 mu M) but not IL-8 production from human fibroblasts (gingival and dermal) and umbilical vein endothelial cells. IL-1 induction of stead y state level of IL-6 mRNA was not significantly inhibited, which is c onsistent with p38 MAPK regulating IL-6 production at the translationa l level. SB 203580 strongly inhibited IL-1-stimulated PC production by fibroblasts and human umbilical vein endothelial cells. This was asso ciated with the inhibition of the induction of PGH synthase-2 protein and mRNA. SE 203580 also inhibited the stimulation of collagenase-1 an d stromelysin-1 production by IL-1 without affecting synthesis of the tissue inhibitor of metalloproteinases (TIMP)-1. SE 203580 prevented t he increase in collagenase-1 and stromelysin-1 mRNA stimulated by IL-1 . In a model of cartilage breakdown, short-term IL-1-stimulated proteo glycan resorption and inhibition of proteoglycan synthesis were unaffe cted by SE 203580, while longer term collagen breakdown was prevented. It is concluded that 1) p38 MAPK plays an important role in the regul ation of some, but not all, responses to IL-1, and 2) it is involved i n the regulation of mRNA levels of some IL-1-responsive genes.