Cyclic AMP increases endogenous granulocyte colony-stimulating factor formation in monocytes and THP-1 macrophages despite attenuated TNF-alpha formation
Cyclic AMP increases endogenous granulocyte colony-stimulating factor formation in monocytes and THP-1 macrophages despite attenuated TNF-alpha formation
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2003
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European Journal of Immunology ; 33 (2003), 8. - pp. 2287-2296. - ISSN 0014-2980. - eISSN 1521-4141
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 aply 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-α formation, we investigated whether drugs suppressing TNF-α 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 E2 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-α and cyclooxygenase products, exerting effects via cAMP and the CREin the G-CSF promoter. This might have bearing for drug side effects, putative G-CSF mimetics and our understanding of G-CSF immunobiology.
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570 Biosciences, Biology
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Granulocyte colony-stimulating factor,cAMP-responsive element,TNF-alpha,Prostaglandin E2,Monocyte
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HARENG, Lars, Thomas MEERGANS, Sonja von AULOCK, Hans-Dieter VOLK, Thomas HARTUNG, 2003. Cyclic AMP increases endogenous granulocyte colony-stimulating factor formation in monocytes and THP-1 macrophages despite attenuated TNF-alpha formation. In: European Journal of Immunology. 33(8), pp. 2287-2296. ISSN 0014-2980. eISSN 1521-4141. Available under: doi: 10.1002/eji.200323923BibTex
@article{Hareng2003Cycli-1230, year={2003}, doi={10.1002/eji.200323923}, title={Cyclic AMP increases endogenous granulocyte colony-stimulating factor formation in monocytes and THP-1 macrophages despite attenuated TNF-alpha formation}, number={8}, volume={33}, issn={0014-2980}, journal={European Journal of Immunology}, pages={2287--2296}, author={Hareng, Lars and Meergans, Thomas and Aulock, Sonja von and Volk, Hans-Dieter and Hartung, Thomas} }
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