on August 17, 2006
Published online before print August 17, 2006, doi: 10.1161/01.ATV.0000241572.05292.fb
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Submitted on May 31, 2006
Accepted on August 4, 2006
C-Reactive Protein Decreases Interleukin-10 Secretion in Activated Human Monocyte-Derived Macrophages via Inhibition of Cyclic AMP Production
Uma Singh ;
From the Laboratory for Atherosclerosis and Metabolic Research (U.S., S.D., M.R.D., D.C., I.J.), University of California, Davis Medical Center, Sacramento; and Department of Medicine (J.R.), University of Colorado Health Sciences Center, Denver.
* To whom correspondence should be addressed. E-mail: ishwarlal.jialal{at}ucdmc.ucdavis.edu.
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 
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.
Key words: CRP • antiinflammatory cytokine • IL-10 • HMDM • atherosclerosis
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