Roles of an IκB Kinase-related Pathway in Human Cytomegalovirus-infected Vascular Smooth Muscle Cells A MOLECULAR LINK IN PATHOGEN-INDUCED PROATHEROSCLEROTIC CONDITIONS

摘要: Viral and bacterial pathogens have long been suspected to affect atherogenesis directly. However, mechanisms linking innate immunity chronic inflammatory diseases such as atherosclerosis are still poorly defined. Here we show that infection of primary human aortic smooth muscle cells (HAOSMC) with cytomegalovirus (HCMV) leads activation the novel IkappaB kinase (IKK)-related kinase, Tank-binding kinase-1 (TBK1), a major effector cellular immune response. We demonstrate part HCMV response is most likely mediated via this because canonical IKK complex was only activated upon HAOSMC. An increase in TBK1 phosphotransferase activity led strong interferon regulatory factor (IRF)-3 transcription measured by its C-terminal phosphorylation, dimerization, DNA binding activity. In addition TBK1, HAOSMC also express another IKK-related isoform, IKKepsilon, albeit at lower level. Nevertheless, both isoforms were required for full IRF-3 HCMV. The transcripts proatherosclerotic genes Ccl5 (encoding chemokine RANTES (regulated activation, normal T cell expressed secreted)) Cxcl10 IP-10 (interferon-gamma-inducible protein 10)) induced an IRF-3-dependent manner after cells. addition, cytokine arrays analysis showed predominant chemokines present supernatant HCMV-infected Activation TBK1/IRF-3 pathway independent epidermal growth receptor pertussis toxin-sensitive G protein-coupled activation. Our results thus add additional molecular clues possible role modulator through induction proinflammatory is, part, dependent pathway.