INTERLEUKIN-1-BETA INDUCTION OF MITOGEN-ACTIVATED PROTEIN-KINASES IN HUMAN MESANGIAL CELLS - ROLE OF OXIDATION

Interleukin-1 beta (IL-1 beta) significantly influences renal cellular function through the induction of several gene products, The molecula r mechanisms involved in gene regulation by IL-1 beta are poorly under stood; however, the appearance of novel tyrosine phosphoproteins in IL -1 beta-treated cells suggests that IL-1 beta may function through tyr osine phosphoprotein intermediates, The mitogen-activated protein (MAP ) kinases are tyrosine phosphoproteins that could potentially mediate the effects of IL-1 beta, Protein tyrosine phosphorylation following I L-1 beta treatment may be dependent on redox changes since the IL-1 be ta receptor is not a protein-tyrosine kinase and oxidation has been sh own to induce tyrosine phosphorylation, In this report we demonstrate that conditioning human glomerular mesangial cells with IL-1 beta resu lts in the tyrosine phosphorylation and activation of two members of t he MAP kinase family, extracellular signal-regulated protein kinase 2 (ERK2) and p54 Jun-NH2-terminal kinase (JNK), This effect of IL-1 beta is abrogated by pretreating cells with the antioxidants N-acetyl-L-cy steine or dithiothreitol, Furthermore, the effects of IL-1 beta on ERK and JNK activation are reproduced by treating mesangial cells with me mbrane-permeable oxidants, IL-1 beta and oxidants also cause phosphory lation and activation of the upstream ERK regulatory element MAP kinas e kinase. Interestingly, IL-1 beta, but not exogenous oxidants, causes phosphorylation of the upstream JNK activator, JNK kinase. These data indicate that IL-1 beta activates ERK2 through an oxidation-dependent pathway, Exogenous oxidants and IL-1 beta activate JNK through differ ent upstream mechanisms; however, antioxidant inhibition of JNK activa tion indicates that endogenous oxidants may play a role in IL-1 beta-i nduced JNK activation, Thus IL-1 beta may affect mesangial cell functi on by activating MAP kinases, which can then regulate gene transcripti on, Furthermore, reactive oxygen species released during inflammatory glomerular injury may also affect mesangial function through a MAP kin ase signal.