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

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 gamma 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.