C-Reactive protein decreases interleukin-10 secretion in activated human monocyte-derived macrophages via inhibition of cyclic AMP production

Uma Singh, Sridevi Devaraj, Mohan R. Dasu, Dana Ciobanu, Jane Reusch, Ishwarlal Jialal

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

OBJECTIVE - C-Reactive protein (CRP), a cardiovascular risk marker, could also participate in atherosclerosis. Atherosclerotic plaques express CRP and interleukin (IL)-10, a major antiinflammatory cytokine. IL-10 deficiency results in increased lesion formation, whereas IL-10 delivery attenuates lesions. We tested the effect of CRP on lipopolysaccharide (LPS)-induced IL-10 secretion in human monocyte-derived macrophages (HMDMs). METHODS AND RESULTS - Incubation of HMDMs with CRP significantly decreased LPS-induced IL-10 mRNA and intracellular and secreted IL-10 protein and destabilized IL-10 mRNA. Also, CRP alone increased secretion of IL-8, IL-6, and tumor necrosis factor from HMDMs and did not inhibit LPS-induced secretion of these cytokines. Fc γ receptor I antibodies significantly reversed CRP-mediated IL-10 inhibition. CRP significantly decreased intracellular cAMP, phospho-cAMP response element binding protein (pCREB), and adenyl cyclase activity. cAMP agonists reversed CRP-mediated IL-10 inhibition. Overexpression of wild-type and constitutively active CREB in THP-1 cells revealed attenuation of the inhibitory effect of CRP on LPS-induced IL-10 levels. CRP also inhibited hemoglobin:haptoglobin-induced IL-10 and heme oxygenase-1. Furthermore, administration of human CRP to rats significantly decreased IL-10 levels. CONCLUSIONS - This study provides novel evidence that CRP, by decreasing IL-10 alters the antiinflammatory/ proinflammatory balance, accentuating inflammation, which is pivotal in atherothrombosis.

Original languageEnglish (US)
Pages (from-to)2469-2475
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume26
Issue number11
DOIs
StatePublished - Nov 2006

Keywords

  • Antiinflammatory cytokine
  • Atherosclerosis
  • CRP
  • HMDM
  • IL-10

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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