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).


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.
Singh
Uma
U
Laboratory for Atherosclerosis and Metabolic Research, University of California, Davis Medical Center, Sacramento, CA 95817, USA.
Devaraj
Sridevi
S
Dasu
Mohan R
MR
Ciobanu
Dana
D
Reusch
Jane
J
Jialal
Ishwarlal
I
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002097:C-Reactive Protein / Q000494:pharmacology*; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006242:Haptoglobins / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors; D006454:Hemoglobins / Q000494:pharmacology; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D017452:Receptors, IgG / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000067956:Adenylyl Cyclase Inhibitors; D000906:Antibodies; D017362:Cyclic AMP Response Element-Binding Protein; C489017:FCGR1A protein, human; D006242:Haptoglobins; D006454:Hemoglobins; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; C035492:haptoglobin-hemoglobin complex; D016753:Interleukin-10; D002097:C-Reactive Protein; D000242:Cyclic AMP; D051547:Heme Oxygenase-1; D050882:CREB-Binding Protein