title: cAMP inhibition of interleukin-1-induced interleukin-6 production by human lung fibroblasts.
abstract: We characterized the effects of agents that alter intracellular adenosine 3',5'-cyclic monophosphate (cAMP) on the interleukin (IL)-6 production of human lung fibroblasts. Unstimulated fibroblasts did not produce significant amounts of IL-6. Recombinant (r) tumor necrosis factor (TNF) weakly stimulated, recombinant interleukin-1-alpha (rIL-1 alpha) strongly stimulated, and rIL-1 alpha and rTNF in combination synergistically augmented fibroblast IL-6 production. Prostaglandin (PG)E1, forskolin, dibutyryl cAMP (DBcAMP), 3-isobutyl-1-methylxanthine (IBMX), and cholera toxin did not cause a detectable alteration in the IL-6 production of unstimulated fibroblasts. However, these agents inhibited the IL-6 production of rIL-1 and rIL-1 plus rTNF-stimulated cells. These effects were dose dependent with a concentration of 2 x 10(-9) M PGE1, 5 x 10(-6) M forskolin, 5 x 10(-4) M DBcAMP, and 1 x 10(-3) M IBMX decreasing rIL-1 alpha (2.5 ng/ml)-induced IL-6 production by approximately 50%. The inhibitory effects of these agents, correlated with their ability to induce fibroblast cAMP accumulation, could not be explained by alterations in cell number or viability and were appreciable even when cAMP modifiers were added to fibroblast culture, 1 h after rIL-1. They were also at least partly specific for rIL-1, since these agents increased the IL-6 production of rTNF-stimulated cells. These cAMP-induced alterations in IL-6 production were associated with corresponding alterations in IL-6 mRNA accumulation. Nuclear run-on analysis demonstrated that the inhibitory effects of PGE1 were associated with a comparable decrease in IL-6 transcription. Agents that increase the levels of intracellular cAMP inhibit rIL-1-induced IL-6 by human lung fibroblasts.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510-8040.
authors.forename: R J
authors.initials: RJ
authors.lastname: Zitnik
authors.forename: T
authors.initials: T
authors.lastname: Zheng
authors.forename: J A
authors.initials: JA
authors.lastname: Elias
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D002460:Cell Line; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism*; D008168:Lung / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D003994:Bucladesine; D002772:Cholera Toxin; D000242:Cyclic AMP; D000527:Alprostadil; D015056:1-Methyl-3-isobutylxanthine