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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2469.)
© 2006 American Heart Association, Inc.

Vascular Biology

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

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 VA Medical Center, Mather (I.J.) and Department of Medicine (J.R.), University of Colorado Health Sciences Center, Denver.

Correspondence to I. Jialal, MD, PhD, Director, Laboratory for Atherosclerosis and Metabolic Research, University of California, Davis Medical Center, 4635, 2nd Ave, Res Bldg 1, Sacramento, CA 95817. 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.

CRP treatment of HMDMs significantly decreased LPS-induced IL-10 mRNA and intracellular and secreted IL-10 protein and destabilized IL-10 mRNA. CRP significantly decreased intracellular cAMP and pCREB. Thus, CRP inhibits LPS-induced IL-10 secretion via inhibition of cAMP production.

Key Words: CRP • antiinflammatory cytokine • IL-10 • HMDM • atherosclerosis

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