This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 26/11/2469    most recent 01.ATV.0000241572.05292.fbv1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Singh, U. Articles by Jialal, I. Search for Related Content PubMed PubMed Citation Articles by Singh, U. Articles by Jialal, I.

(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

This article has been cited by other articles:

				S. U. Eisenhardt, J. Habersberger, A. Murphy, Y.-C. Chen, K. J. Woollard, N. Bassler, H. Qian, C. von zur Muhlen, C. E. Hagemeyer, I. Ahrens, et al. Dissociation of Pentameric to Monomeric C-Reactive Protein on Activated Platelets Localizes Inflammation to Atherosclerotic Plaques Circ. Res., July 17, 2009; 105(2): 128 - 137. [Abstract] [Full Text] [PDF]

				S. Devaraj, U. Singh, and I. Jialal The Evolving Role of C-Reactive Protein in Atherothrombosis Clin. Chem., February 1, 2009; 55(2): 229 - 238. [Abstract] [Full Text] [PDF]

				S. Devaraj, N. Torok, M. R. Dasu, D. Samols, and I. Jialal Adiponectin Decreases C-Reactive Protein Synthesis and Secretion From Endothelial Cells: Evidence for an Adipose Tissue-Vascular Loop Arterioscler Thromb Vasc Biol, July 1, 2008; 28(7): 1368 - 1374. [Abstract] [Full Text] [PDF]

				E. A. Van Vre, H. Bult, V. Y. Hoymans, V. F.I. Van Tendeloo, C. J. Vrints, and J. M. Bosmans Human C-Reactive Protein Activates Monocyte-Derived Dendritic Cells and Induces Dendritic Cell-Mediated T-Cell Activation Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): 511 - 518. [Abstract] [Full Text] [PDF]

				E. Grad, M. Golomb, I. Mor-Yosef, N. Koroukhov, C. Lotan, E. R. Edelman, and H. D. Danenberg Transgenic expression of human C-reactive protein suppresses endothelial nitric oxide synthase expression and bioactivity after vascular injury Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H489 - H495. [Abstract] [Full Text] [PDF]

				G. Fantuzzi and T. Mazzone Adipose Tissue and Atherosclerosis: Exploring the Connection Arterioscler Thromb Vasc Biol, May 1, 2007; 27(5): 996 - 1003. [Abstract] [Full Text] [PDF]

				M. R. Dasu, S. Devaraj, T. W. Du Clos, and I. Jialal The biological effects of CRP are not attributable to endotoxin contamination: evidence from TLR4 knockdown human aortic endothelial cells J. Lipid Res., March 1, 2007; 48(3): 509 - 512. [Abstract] [Full Text] [PDF]

				M. A. Punchard, A. O. Pozzi, T. P. de Prada, M. T. Coronado, P. Gonzalez, and P. Fantidis Letter to the Editor: Monocyte cAMP Content Is Decreased in Patients With Stable Angina Arterioscler Thromb Vasc Biol, February 1, 2007; 27(2): 436 - 437. [Full Text] [PDF]