REVIEW The cytokine Tumor necrosis factor-alpha (TNF-alpha)is secreted by activated monocytes/macrophages and T lymphocytes and has been implicated in several disease states, including rheumatoid arthritis, inflammatory bowel disease, septic shock, and osteoporosis. Monocyte/macrophage production of TNF-alpha is dependent on the mitogen-activated protein kinase p38. The compound RWJ 67657 is a potent, orally active inhibitor of MAPK and it inhibited the release of TNF-alpha from LPA stimulated human mononuclear cells with an IC(50) of 3 nM, as well as the release of TNF-alpha from peripheral blood mononuclear cells treated with the T cell stimulator and superantigen staphylococcal enterotoxin B with an IC(50) value of 13 nM. Also RWJ 67657 was approximately 10-fold more potent than the literature standard p38 kinase inhibitor SB 203580 in all p38 dependent in vitro systems tested and is much more specific than SB 203580 for p38 kinases. RWJ 67657 inhibited the enzymatic activity of recombinant p38alpha and beta, with in vitro IC50 values of 1 and 11 µM respectively, but not gamma or delta, and in further in vitro test across a panel of other enzymes RWJ 67657 demonstrated no other significant activity.
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