Up-regulation of monocytic IL-10 by tumor necrosis factor-alpha and cAMP elevating drugs

Int Immunol. 1995 Apr;7(4):517-23. doi: 10.1093/intimm/7.4.517.


It is well established that endotoxin [lipopolysacharide (LPS)] induces pro-inflammatory cytokine production in monocytes, which is followed by secretion of the anti-inflammatory cytokine, IL-10. IL-10 down-regulates inflammatory response [tumor necrosis factor (TNF)-alpha, IL-1, IL-6, IL-8] as well as IL-10 synthesis itself. We wondered whether pro-inflammatory cytokines such as TNF-alpha may be involved in the regulation of human IL-10 synthesis. TNF-alpha induced de novo IL-10 mRNA expression in a dose-dependent manner but no IL-10 protein in human peripheral blood mononuclear cells. Furthermore, LPS-induced IL-10 gene and protein expression was significantly inhibited by neutralizing anti-TNF-alpha mAb. On the basis of these results, we conclude that TNF-alpha is involved in the up-regulation of its antagonist IL-10. Paradoxically, drugs that effectively inhibit expression of TNF-alpha via the elevation of intracellular cAMP level (iloprost, pentoxifylline, prostaglandin E2 and N6,2-O-dibutyryl cAMP) augmented the endotoxin-induced IL-10 synthesis at both protein and mRNA levels. In order to provide a basis for the analysis of the transcriptional regulation of the human IL-10 gene, we isolated a fragment of the human IL-10 gene containing 1308 bp of the 5' non-coding sequence. It shows remarkable homology to the mouse IL-10 promoter in regions that have been associated with transcriptional regulation, including a cAMP responsive element which could explain the cAMP-mediated effects. The lack of a NF-kappa B-like binding site in the human sequence suggests a NF-kappa B-independent mechanism of TNF-alpha-induced IL-10 gene activation.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cyclic AMP / biosynthesis*
  • Cyclic AMP / physiology
  • Humans
  • Iloprost / pharmacology
  • Interleukin-10 / biosynthesis*
  • Interleukin-10 / genetics
  • Mice
  • Molecular Sequence Data
  • Monocytes / drug effects*
  • Monocytes / metabolism
  • Promoter Regions, Genetic
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / physiology*
  • Up-Regulation / drug effects*
  • Up-Regulation / immunology


  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Cyclic AMP
  • Iloprost

Associated data

  • GENBANK/X73536
  • GENBANK/Z30175