THE MITOGEN-ACTIVATED PROTEIN KINASE p38 IS NECESSARY FOR INTERLEUKIN-1β-INDUCED MONOCYTE CHEMOATTRACTANT PROTEIN 1 EXPRESSION BY HUMAN MESANGIAL CELLS

Mitogen-activated protein (MAP) kinases have been suggested as potential mediators for interleukin 1β (IL-1β)-induced gene activation. This study investigated the role of the MAP kinases p38 and ERK2 in IL-1β-mediated expression of the chemokine MCP-1 by human mesangial cells. Phosphorylation of p38 kinase, which is necessary for activation, increased significantly after IL-1β treatment. p38 kinase immunoprecipitated from IL-1β-treated cells phosphorylated target substrates to a greater extent than p38 kinase from controls. SB 203580, a selective p38 kinase inhibitor, was used to examine the role of p38 kinase in MCP-1 expression. SB 203580 decreased IL-1β-induced MCP-1 mRNA and protein levels, but did not affect MCP-1 mRNA stability. Because NF-κB is necessary for MCP-1 gene expression, the effect of p38 kinase inhibition on IL-1β induction of NF-κB was measured. SB 203580 (up to 25 μM) had no effect on IL-1β-induced NF-κB nuclear translocation or DNA binding activity. Our previous work showed that IL-1β also activates the MAP kinase ERK2 in human mesangial cells. PD 098059, a selective inhibitor of the ERK activating kinase MEK1, had no effect on IL-1β-induced MCP-1 mRNA or protein levels, or on IL-1β activation of NF-κB. These data indicate that p38 kinase is necessary for the induction of MCP-1 expression by IL-1β, but is not involved at the level of cytoplasmic activation of NF-κB. In contrast, ERK2 does not mediate IL-1β induced MCP-1 gene expression.