Cyclic AMP increases endogenous granulocyte colony-stimulating factor formation in monocytes and THP-1 macrophages despite attenuated TNF-α formation

Lars Hareng, Thomas Meergans, Sonja von Aulock, Hans Dieter Volk, Thomas Hartung

Research output: Contribution to journalReview articlepeer-review

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-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 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.

Original languageEnglish (US)
Pages (from-to)2287-2296
Number of pages10
JournalEuropean Journal of Immunology
Volume33
Issue number8
DOIs
StatePublished - Aug 1 2003
Externally publishedYes

Keywords

  • Granulocyte colony-stimulating factor
  • Monocyte
  • Prostaglandin E
  • TNF-α
  • cAMP-responsive element

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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