title: Inhibition of the arachidonic acid pathway prevents induction of IL-8 mRNA by phorbol ester and changes the release of IL-8 from HL 60 cells: differential inhibition of induced expression of IL-8, TNF-alpha, IL-1 alpha, and IL-1 beta.
abstract: The promyelocytic HL 60 cell line can be used as an in vitro model system to study hematopoetic cell differentiation and inflammatory events. We studied the signal transduction pathway of induced interleukin (IL)-8 expression and compared it with those of tumor necrosis factor alpha (TNF-alpha), IL-1 alpha, and IL-1 beta. The differentiation of HL 60 cells to macrophage-like cells by PMA resulted in a rapid and marked induction of these inflammatory cytokines. The up-regulation occurred in the absence of ongoing protein synthesis, but cycloheximide-sensitive gene products modulated their induction kinetics. Staurosporine, a potent inhibitor of protein kinases, strongly inhibited their gene expression. Phosphorylation may not act directly on latent transcription factors, since bromophenacyl bromide, an inhibitor for the release of arachidonic acid from phorbol-12 myristate 13-acetate (PMA)-stimulated HL 60 cells, markedly depressed the induced mRNAs for IL-8, TNF-alpha, and IL-1 alpha and -beta. Similarly, 5,8,11,14 eicosatetraynoic acid (ETYA), another inhibitor of the arachidonic acid pathway, blocked the induction of transcripts for TNF-alpha, and both IL-1 genes in phorbol ester-stimulated HL 60 cells. In contrast, ETYA increased the induced IL-8 RNA levels and stimulated the release for IL-8. Also, ketoconazole, an inhibitor of 5-lipoxygenase and indomethacin, an inhibitor of cyclooxygenases did not block the induction of IL-8 mRNA. However, the release of IL-8 protein was regulated by indomethacin and ketoconazole. Our results indicate that arachidonic acid metabolites are mediators in the signal transduction pathway of IL-8 expression and that the involved second messengers are different from those which are important for the induction of TNF-alpha and IL-1 beta expression.
authors.affiliation: Institute of Pathology, University of Freiburg, Germany.
authors.forename: R W
authors.initials: RW
authors.lastname: Meier
authors.forename: G
authors.initials: G
authors.lastname: Niklaus
authors.forename: B
authors.initials: B
authors.lastname: Dewald
authors.forename: M F
authors.initials: MF
authors.lastname: Fey
authors.forename: A
authors.initials: A
authors.lastname: Tobler
mesh_terms: D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000098:Acetophenones / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000494:pharmacology; D007375:Interleukin-1 / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D007975:Leukotriene B4 / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D000098:Acetophenones; D000470:Alkaloids; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D007375:Interleukin-1; D016209:Interleukin-8; D016859:Lipoxygenase Inhibitors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015117:5,8,11,14-Eicosatetraynoic Acid; D007975:Leukotriene B4; D016718:Arachidonic Acid; D003513:Cycloheximide; D011493:Protein Kinase C; D010741:Phospholipases A; D019311:Staurosporine; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; C006821:4-bromophenacyl bromide