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.