IL-6 is produced by splenocytes derived from CMV-infected mice in response to CMV antigens, and induces MCP-1 production by endothelial cells: a new mechanistic paradigm for infection-induced atherogenesis.
Atherosclerosis is an inflammatory disease. One of the candidate inflammatory triggers is infection. To further characterize the interaction between infection, cytokine induction, and atherosclerosis, we tested the hypothesis that cytomegalovirus (CMV) infection induces the pro-inflammatory cytokine interleukin-6 (IL-6), which in turn induces "pro-atherosclerotic" changes in vascular endothelial cells (ECs). ELISA was used to determine the levels of monocyte chemoattractant protein-1 (MCP-1) in the supernatant of mouse and human ECs incubated with IL-6, and IL-6 levels in supernatants of splenocytes, derived from CMV-infected and uninfected mice, stimulated with mice CMV antigens. IL-6 induced, in a dose response fashion, MCP-1 expression in human ECs: 0, 2, 10, and 50 pg/ml IL-6 increased MCP-1 levels in EC conditioned medium from 1120+/-65 to 1148+/-105, 1395+/-40, and 2119+/-130 pg/ml, respectively (P<0.001). IL-6 also induced MCP-1 expression in mouse ECs (P<0.002). Importantly, IL-6 concentration in the supernatants of splenocytes stimulated with CMV antigens rose from undetectable levels in uninfected mice to 14.9+/-5 pg/ml in the infected mice (P<0.04). These results suggest a previously unrecognized, but potentially important mechanism whereby CMV, and other pathogens, contribute to atherogenesis: T lymphocytes, clonally expanded in response to antigens presented by CMV infection, home to sites of vascular injury and locally release IL-6 when presented with either pathogen antigens that may be present in the plaque, or when they cross-react with host peptides homologous to the relevant pathogen antigens; IL-6 then triggers ECs to release MCP-1, which recruits more monocytes and T-cells into the vessel wall and thereby exacerbates local inflammation, and thus atherogenesis.
Rott
David
D
Cardiovascular Research Institute, Medstar Research Institute, Washington Hospital Center, 108 Irving Street, NW, GHRB 217, 20010, Washington, DC, USA
Zhu
Jianhui
J
Zhou
Yi Fu
YF
Burnett
Mary Susan
MS
Zalles-Ganley
Alexandra
A
Epstein
Stephen E
SE
D000818:Animals; D000914:Antibodies, Viral / Q000032:analysis; D000956:Antigens, Viral / Q000276:immunology*; D001161:Arteriosclerosis / Q000821:virology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
D000914:Antibodies, Viral; D000956:Antigens, Viral; D018932:Chemokine CCL2; D015850:Interleukin-6; D007371:Interferon-gamma