herbimycin and Arthritis--Rheumatoid

The histological features of rheumatoid arthritis (RA) consist of overgrowth of synovial cells. Several growth factors that cause synovial hyperplasia have been identified in RA synovium. The basic-fibroblast growth factor (b-FGF), representing one of these growth factors, may play an important role in the pathogenesis of RA. We examined the b-FGF-mediated intracellular signal pathway involved in synovial cell growth. b-FGF-induced synovial cell growth was inhibited by protein tyrosine kinase (PTK) inhibitors, herbimycin A and genistein, but not by H7 that inhibits protein kinase C (PKC). Stimulation of synovial cells with b-FGF resulted in tyrosine phosphorylation of cellular proteins and MAP kinase activation. Our results also demonstrated that b-FGF-mediated activation of MAP kinase was inhibited by herbimycin A indicating that protein tyrosine kinase may be involved in the activation of MAP kinase in human synovial cells. However, inhibition of b-FGF-mediated MAP kinase activation by PKC downregulation did not occur.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Arthritis, Rheumatoid; Benzoquinones; Calcium-Calmodulin-Dependent Protein Kinases; Cell Cycle; Cell Division; Cells, Cultured; Fibroblast Growth Factor 2; Fibroblasts; Genistein; Humans; Hyperplasia; Isoflavones; Isoquinolines; Kinetics; Lactams, Macrocyclic; Piperazines; Protein Kinase C; Protein Kinases; Protein-Tyrosine Kinases; Quinones; Rifabutin; Signal Transduction; Synovial Membrane; Thymidine