TY - JOUR T1 - Differential regulation of human monocyte-derived TNF alpha and IL-1 beta by type IV cAMP-phosphodiesterase (cAMP-PDE) inhibitors. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1313 LP - 1320 VL - 272 IS - 3 AU - M W Verghese AU - R T McConnell AU - A B Strickland AU - R C Gooding AU - S A Stimpson AU - D P Yarnall AU - J D Taylor AU - P J Furdon Y1 - 1995/03/01 UR - http://jpet.aspetjournals.org/content/272/3/1313.abstract N2 - Elevation of cAMP downregulates certain functions of inflammatory cells, including the release of TNF alpha and IL-1 beta by macrophages. Intracellular cAMP levels can be modulated pharmacologically by adding cell-permeable cAMP analogs, by stimulating adenylate cyclase or by inhibiting degradation of cAMP by cAMP-phosphodiesterases (cAMP-PDE). Multiple forms of cAMP-PDEs have been identified in various tissues and cells using both biochemical characterization and selective inhibitors. Therefore, we wanted to determine which of these different PDE isoforms was present in human monocytes and whether this isoform could regulate cytokine release from human monocytes by a mechanism similar to that seen with dbcAMP or PGE1. Our results demonstrate that selective inhibitors of type IV cAMP-PDE, such as rolipram and Ro20-1724, are clearly the most effective compounds at enhancing cAMP levels and inhibiting the release of TNF alpha and IL-1 beta in these cells. The type III cAMP-PDE-selective inhibitors C1930 and cilostamide and the nonselective PDE inhibitors IBMX and pentoxifylline were significantly less potent. In agreement with these data, cAMP-PDE activity in cytosolic extracts from human monocytes was also much more sensitive to inhibition by rolipram than by cilostamide. Additionally, rolipram dramatically reduced TNF alpha mRNA accumulation, which supports previous findings that cAMP regulates TNF alpha at the transcriptional level. Surprisingly, rolipram, rolipram, dbcAMP or PGE1 increased IL-1 beta was reduced, which indicates that cAMP can have both positive and negative effects on the regulation of IL-1 beta.(ABSTRACT TRUNCATED AT 250 WORDS) ER -