Interleukin-1-induced IL-8 and IL-6 gene expression and production in human mesangial cells is differentially regulated by cAMP

Kidney Int. 1995 Dec;48(6):1767-77. doi: 10.1038/ki.1995.475.


We have previously proposed that activated mesangial cells (MC) have a direct role in the initiation and propagation of inflammatory events within the glomerulus via the generation of the mesangioproliferative cytokine IL-6 and the chemokines IL-8 and MCP-1. The objective of this study was to investigate the role of cAMP in the regulation of IL-6 and IL-8 gene expression and peptide production in IL-1 stimulated human MC. Agents known to elevate cAMP, including dibutyryl cAMP (db-cAMP), forskolin or isobutyl-methylxanthine (IBMX) were alone unable to induce IL-6 or IL-8 expression or production above media control levels, indicating activation of the cAMP pathway could not mimic IL-1 signaling events. In the presence of IL-1, all three agents produced a marked potentiation of IL-6 mRNA expression and dose-dependent increase in IL-6 peptide production (twofold), but had little or no effect on IL-8 mRNA expression or peptide generation. In marked contrast cholera toxin (CT) caused a dose-dependent potentiation of both IL-1-induced IL-6 (approximately fourfold) and IL-8 peptide (approximately twofold) generation. The control agent, the purified binding subunit of cholera toxin (CT-B) which is devoid of ADP-ribosylating activity also enhanced IL-6 and IL-8 (approximately twofold) peptide generation indicating cAMP-independent mechanisms may be involved in the CT up-regulation of these cytokines. Treatment of MC with the cycloxygenase inhibitor indomethacin resulted in partial inhibition (37%) of IL-6 production but had no effect on IL-8 generation. Thus our data show that cAMP can potentiate IL-1 induced IL-6 production, while having no effect on IL-8 induction, and PGE2 may operate via a positive feedback loop to up-regulate IL-1 induced IL-6. Taken together, our results demonstrate that cAMP differentially regulates IL-6 and IL-8 production in IL-1-stimulated human MC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Northern
  • Cells, Cultured
  • Cholera Toxin / pharmacology
  • Cyclic AMP / physiology*
  • Cyclooxygenase Inhibitors / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression / drug effects
  • Glomerular Mesangium / drug effects
  • Glomerular Mesangium / metabolism*
  • Humans
  • Indomethacin / pharmacology
  • Interleukin-1 / pharmacology*
  • Interleukin-6 / biosynthesis*
  • Interleukin-6 / genetics
  • Interleukin-8 / biosynthesis*
  • Interleukin-8 / genetics
  • RNA, Messenger / metabolism


  • Cyclooxygenase Inhibitors
  • Interleukin-1
  • Interleukin-6
  • Interleukin-8
  • RNA, Messenger
  • Cholera Toxin
  • Cyclic AMP
  • Indomethacin