PYRROLIDINE DITHIOCARBAMATE DIFFERENTIALLY AFFECTS CYTOKINE-INDUCED AND CAMP-INDUCED EXPRESSION OF GROUP-II PHOSPHOLIPASE A(2) IN RAT RENAL MESANGIAL CELLS

Renal mesangial cells express group II phospholipase A(2) in response to two principal classes of activating signals that may interact in a synergistic fashion, These two groups of activators comprise inflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) and agents that elevate cellular levels of cAMP such as forskolin, an activator of adenylate cyclase, Using pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of nuclear factor NF kappa B, we determined its role in cytokine - and cAMP - triggered group II PLA(2) expression, Micromolar amounts of PDTC suppress the IL-1 beta- and TNF alpha-dependent, but not the forskolin-stimulated group II PLA(2) activity in mesangial cells, Furthermore, PDTC inhibited the increase of group II PLA(2) mRNA steady state levels in response to IL-1 beta and TNF alpha, while only marginally affecting forskolin-induced PLA(2) mRNA levels, Our data suggest that NF kappa B activation is an essential component of the cytokine signalling pathway responsible for group II PLA(2) gene regulation and that cAMP triggers a separate signalling cascade not involving NF kappa B. These observations may provide a basis to study the underlying mechanisms involved in the regulation of group II PLA(2) gene expression.