title: Pyrrolidine dithiocarbamate differentially affects cytokine- and cAMP-induced expression of group II phospholipase A2 in rat renal mesangial cells.
abstract: Renal mesangial cells express group II phospholipase A2 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 PLA2 expression. Micromolar amounts of PDTC suppress the IL-1 beta- and TNF alpha-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-1 beta and TNF alpha, while only marginally affecting forskolin-induced PLA2 mRNA levels. Our data suggest that NF kappa B 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 NF kappa B. These observations may provide a basis to study the underlying mechanisms involved in the regulation of group II PLA2 gene expression.
authors.affiliation: Department of Pharmacology, University of Basel, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Walker
authors.forename: D
authors.initials: D
authors.lastname: Kunz
authors.forename: W
authors.initials: W
authors.lastname: Pignat
authors.forename: H
authors.initials: H
authors.lastname: van den Bosch
authors.forename: J
authors.initials: J
authors.lastname: Pfeilschifter
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000201:enzymology*; D007375:Interleukin-1 / Q000494:pharmacology; D010741:Phospholipases A / Q000145:classification / Q000235:genetics*; D054467:Phospholipases A2; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013859:Thiocarbamates / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D007375:Interleukin-1; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; C020972:pyrrolidine dithiocarbamic acid; D000242:Cyclic AMP; D010741:Phospholipases A; D054467:Phospholipases A2