CRP promotes monocyte-endothelial cell adhesion via Fcgamma receptors in human aortic endothelial cells under static and shear flow conditions.
Monocyte-endothelial cell adhesion is a key early event in atherogenesis. C-reactive protein (CRP), a cardiovascular risk marker, is known to stimulate ICAM and VCAM in human aortic endothelial cells (HAEC) and induces monocyte-endothelial cell adhesion. In this study, we examined the mechanisms by which native CRP promotes monocyte-endothelial cell adhesion under static conditions and tested the effect of CRP on adhesion under shear flow. Incubation of HAEC with CRP (>25 microg/ml) upregulated NF-kappaB activity, and this resulted in a significant increase in ICAM (54% increase, P<0.001), VCAM (41% increase, P<0.01), and monocyte-endothelial cell adhesion (44% increase, P<0.02) compared with those of control. Preincubation with antibodies to CD32 and CD64 but not CD16 effectively inhibited this activation. Blocking NF-kappaB activity with inhibitors or a dominant negative inhibitory kappaB significantly decreased ICAM, VCAM upregulation, and subsequent monocyte-endothelial cell adhesion. Preincubation with antibodies to CD32 and CD64 or transient transfection with small interference RNA to CD32 attenuated CRP-induced NF-kappaB activity, ICAM, VCAM, and monocyte-endothelial cell adhesion under static conditions. Also, the Syk kinase inhibitor piceatannol and MG-132, a proteasome degradation inhibitor, produced similar attenuation in NF-kappaB activity, ICAM, VCAM, and adhesion. Furthermore, CRP-activated endothelial cells supported monocyte rolling, arrest, and transmigration in shear flow (2 dyn/cm2), and this was also inhibited by preincubation with antibodies to CD32 and CD64. Thus, in HAEC, CRP upregulates monocyte-endothelial adhesion by activation of NF-kappaB through engaging the Fcgamma receptors CD32 and CD64.
Devaraj
Sridevi
S
Laboratory for Atherosclerosis and Metabolic Research, 4635 II Ave., Res. 1 Bldg., Rm. 3000, University of California Davis Medical Center, Sacramento, CA 95817, USA.
Davis
Benjamin
B
Simon
Scott I
SI
Jialal
Ishwarlal
I
D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000502:physiology; D002097:C-Reactive Protein / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
D000906:Antibodies; D019040:E-Selectin; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017452:Receptors, IgG; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D002097:C-Reactive Protein