Exclusive Temporal Stimulation of IL-10 Expression in LPS-Stimulated Mouse Macrophages by cAMP Inducers and Type I Interferons

Orna Ernst, Yifat Glucksam-Galnoy, Bibek Bhatta, Muhammad Athamna, Iris Ben-Dror, Yair Glick, Doron Gerber, Tsaffrir Zor

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Expression of the key anti-inflammatory cytokine IL-10 in lipopolysaccharide (LPS)-stimulated macrophages is mediated by a delayed autocrine/paracrine loop of type I interferons (IFN) to ensure timely attenuation of inflammation. We have previously shown that cAMP synergizes with early IL-10 expression by LPS, but is unable to amplify the late type I IFN-dependent activity. We now examined the mechanism of this synergistic transcription in mouse macrophages at the promoter level, and explored the crosstalk between type I IFN signaling and cAMP, using the β-adrenergic receptor agonist, isoproterenol, as a cAMP inducer. We show that silencing of the type I IFN receptor enables isoproterenol to synergize with LPS also at the late phase, implying that autocrine type I IFN activity hinders synergistic augmentation of LPS-stimulated IL-10 expression by cAMP at the late phase. Furthermore, IL-10 expression in LPS-stimulated macrophages is exclusively stimulated by either IFNα or isoproterenol. We identified a set of two proximate and inter-dependent cAMP response element (CRE) sites that cooperatively regulate early IL-10 transcription in response to isoproterenol-stimulated CREB and that further synergize with a constitutive Sp1 site. At the late phase, up-regulation of Sp1 activity by LPS-stimulated type I IFN is correlated with loss of function of the CRE sites, suggesting a mechanism for the loss of synergism when LPS-stimulated macrophages switch to type I IFN-dependent IL-10 expression. This report delineates the molecular mechanism of cAMP-accelerated IL-10 transcription in LPS-stimulated murine macrophages that can limit inflammation at its onset.

Original languageEnglish
Pages (from-to)1788
Number of pages1
JournalFrontiers in Immunology
Volume10
DOIs
StatePublished - 1 Jan 2019
Externally publishedYes

Keywords

  • CREB
  • IL-10 expression
  • IL-10 promoter
  • cAMP
  • cAMP response element
  • lipopolysaccharide
  • toll-like receptor 4
  • type I interferons

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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