title: Cyclic AMP increases endogenous granulocyte colony-stimulating factor formation in monocytes and THP-1 macrophages despite attenuated TNF-alpha formation.
abstract: The cytokine granulocyte colony-stimulating factor (G-CSF) is in broad clinical use to treat neutropenia, and trials on its use in immunosuppressed conditions and infections are ongoing. To apply G-CSF effectively, it is crucial to understand the regulation and distribution of its endogenous formation. Since G-CSF release is mediated, at least in part, by TNF-alpha formation, we investigated whether drugs suppressing TNF-alpha also impair G-CSF production. Surprisingly, G-CSF formation was enhanced in lipopolysaccharide (LPS)-stimulated blood from a pentoxifylline-treated patient. In the presence of dibutyryl-cAMP, forskolin, tolafentrine or 3-isobutyl-1-methylxanthine, LPS-induced G-CSF formation was enhanced in THP-1 cells, primary monocytes and whole blood. Correspondingly,rp-8-bromo-cAMP suppressed LPS-induced G-CSF release. Addition of prostaglandin E(2) enhanced and indomethacin suppressed G-CSF formation. Reporter gene studies showed that dibutyryl-cAMP enhanced LPS-induced G-CSF promoter activity, indicating a transcriptional up-regulation. Furthermore, disruption of a newly identified putative cAMP-responsive element (CRE) in the G-CSF promoter demonstrated the regulatory role for G-CSF gene transcription. In conclusion, endogenous G-CSF formation critically depends on both TNF-alpha and cyclooxygenase products, exerting effects via cAMP and the CRE in the G-CSF promoter. This might have bearing for drug side effects, putative G-CSF mimetics and our understanding of G-CSF immunobiology.
authors.affiliation: Biochemical Pharmacology, Universität Konstanz, Konstanz, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Hareng
authors.forename: Thomas
authors.initials: T
authors.lastname: Meergans
authors.forename: Sonja
authors.initials: S
authors.lastname: von Aulock
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000328:Adult; D003994:Bucladesine / Q000494:pharmacology; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009287:Naphthyridines / Q000494:pharmacology; D010431:Pentoxifylline / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D008070:Lipopolysaccharides; D009287:Naphthyridines; D014409:Tumor Necrosis Factor-alpha; C094030:tolafentrine; D016179:Granulocyte Colony-Stimulating Factor; D005576:Colforsin; D003994:Bucladesine; D000242:Cyclic AMP; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D010431:Pentoxifylline; D015056:1-Methyl-3-isobutylxanthine