Immunopharmacological potential of selective phosphodiesterase inhibition. I. Differential regulation of lipopolysaccharide-mediated proinflammatory cytokine (interleukin-6 and tumor necrosis factor-alpha) biosynthesis in alveolar epithelial cells.
In an attempt to elaborate in vitro on a therapeutic strategy that counteracts an inflammatory signal, we previously reported a novel immunopharmacological potential of glutathione, an antioxidant thiol, in regulating inflammatory cytokines. In the present study, we investigated the hypothesis that selective regulation of phosphodiesterases (PDEs), a family of enzymes that controls intracellular cAMP/cGMP degradation, differentially regulates proinflammatory cytokines. Selective PDE1 inhibition (8-methoxymethyl-3-isobutyl-1-methylxanthine) blockaded lipopolysaccharide-endotoxin (LPS)-mediated biosynthesis of interleukin (IL)-6, but this pathway had no inhibitory effect on tumor necrosis factor-alpha (TNF-alpha). Furthermore, inhibition of PDE3 (amrinone) abolished the effect of LPS on IL-6, but attenuated TNF-alpha production. Reversible competitive inhibition of PDE4 (rolipram) exhibited a potent inhibitory effect on IL-6 and a dual, biphasic (excitatory/inhibitory) effect on TNF-alpha secretion. Blockading PDE5 (4-[[3',4'-(methylenedioxy)benzyl] amino]-6-methoxyquinazoline) showed a high potency in reducing IL-6 production, but in a manner similar to the inhibition of PDE4, exhibited a biphasic effect on TNF-alpha biosynthesis. Simultaneous inhibition of PDE5, 6, and 9 (zaprinast), purported to specifically elevate intracellular cGMP, reduced, in a dose-independent manner, IL-6 and TNF-alpha biosynthesis. Finally, nonselective inhibition of PDE by pentoxifylline suppressed LPS-mediated secretion of IL-6 and TNF-alpha. The involvement of specific PDE isoenzymes in differentially regulating LPS-mediated inflammatory cytokine biosynthesis indicates a novel approach to unravel the potential therapeutic targets that these isozymes constitute during the progression of inflammation within the respiratory epithelium.
Haddad
John J
JJ
Neuroscience Research Laboratory, Department of Anesthesia and Perioperative Care, University of California Medical Center, San Francisco, California 94143, USA. jhaddad@itsa.ucsf.edu
Land
Stephen C
SC
Tarnow-Mordi
William O
WO
Zembala
Marek
M
Kowalczyk
Danuta
D
Lauterbach
Ryszard
R
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D012137:Respiratory System / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015850:Interleukin-6; D007527:Isoenzymes; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D010727:Phosphoric Diester Hydrolases