Pyrrolidine dithiocarbamate differentially affects cytokine‐ and cAMP‐induced expression of group II phospholipase A2 in rat renal mesangial cells

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Abstract
Renal mesangial cells express group II phospholipase A2 in response to two principal classes activating signals that may interact in a synergistic fashion. These two groups of activators comprise inflammatory cytokines such as interleukin‐1β (IL‐1β) and tumor necrosis factor‐α (TNFα) 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 NFκB, we determined its role in cytokine — and cAMP — triggered group II PLA2 expression. Micromolar amounts of PDTC suppress the IL‐1β‐ and TNF α‐dependent, but not the forskolin‐stimulated group II PLA2 activity in mesangial cells. Furthermore, PDTC inhibited the increase of group II PLA2 mRNA steady state levels in response to IL‐1β and TNFα, while only marginally affecting forskolin‐induced PLA2 mRNA level. Our data suggest that NFκB activation is an essential component of the cytokine signalling pathway responsible for group II PLA2 gene regulation and that cAMP triggers a separate signalling cascade not involving NFκB. These observations may provide a basis to study the underlying mechanisms involved in the regulation of group II PLA2 gene expression.

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