Pyrrolidine dithiocarbamate differentially affects interleukin 1 beta- and cAMP-induced nitric oxide synthase expression in rat renal mesangial cells.

Inducible nitric oxide synthase (NOS) is expressed in renal mesangial cells in response to two principal classes of activating signals that interact in a synergistic fashion. These two groups of activators comprise inflammatory cytokines such as interleukin 1 (IL-1) or tumour necrosis factor alpha and agents that elevate cellular levels of cAMP. We have used pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of nuclear factor kappa B (NF kappa B), to determine its role in IL-1 beta- and cAMP-triggered NOS expression. Micromolar amounts of PDTC suppress IL-1 beta-, but not cAMP-stimulated nitrite production, the stable end product of NO formation in mesangial cells. Furthermore, PDTC completely inhibited the increase of NOS mRNA in response to IL-1 beta, while only marginally affecting cAMP-induced NOS mRNA levels. Our data suggest that NF kappa B activation is an essential component of the IL-1 beta signalling pathway responsible for NOS gene activation and that cAMP triggers a separate signalling cascade not involving NF kappa B. These observations may provide a basis for the synergistic stimulation of NOS expression by cytokines and cAMP in mesangial cells.