title: Pyrrolidine dithiocarbamate differentially affects interleukin 1 beta- and cAMP-induced nitric oxide synthase expression in rat renal mesangial cells.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Basel, Switzerland.
authors.forename: W
authors.initials: W
authors.lastname: Eberhardt
authors.forename: D
authors.initials: D
authors.lastname: Kunz
authors.forename: J
authors.initials: J
authors.lastname: Pfeilschifter
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D015152:Blotting, Northern; D003994:Bucladesine / Q000494:pharmacology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D004357:Drug Synergism; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects*; D005920:Glomerular Mesangium / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology*
chemical_list: D007375:Interleukin-1; D009573:Nitrites; D011759:Pyrrolidines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D003994:Bucladesine; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases