Tyrosine kinase inhibitors, genistein and herbimycin A, do not block interleukin-1 beta-induced activation of NF-kappa B in rat mesangial cells.

We have previously demonstrated that interleukin-1 beta (IL-1 beta) rapidly induces tyrosine phosphorylation of several proteins in the renal mesangial cell. Two mechanistically distinct tyrosine kinase inhibitors, genistein and herbimycin A, block the induction of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) by IL-1 beta in rat mesangial cells. Since both COX-2 and iNOS promoters have a kappa B binding motif, we have evaluated the effects of tyrosine kinase inhibitors on IL-1 beta-induced nuclear factor-kappa B (NF-kappa B) activation by electromobility shift assays. IL-1 beta rapidly induced the translocation of NF-kappa B in rat mesangial cells. However, the tyrosine kinase inhibitors, genistein and herbimycin A, failed to block the translocation of NF-kappa B at concentrations which abolish COX-2 and iNOS mRNA expression. These data suggest that an upstream tyrosine kinase pathway may not be required for IL-1 beta-induced NF-kappa B activation and that the tyrosine kinase pathway may converge with the NF-kappa B pathway down-stream of NF-kappa B activation in rat mesangial cells.