The molecular mechanisms by which a chronic asymptomatic C. pneumoniae infection might contribute to atherogenesis and lesional complications remain obscure. This study demonstrated that chlamydial HSP 60, produced abundantly during chronic, persistent chlamydial infections, activates human vascular cell and macrophage functions related to atheroma formation and lesional complications.
We aimed to identify possible molecular effectors of C. pneumoniae
contribution to atheroma. HSPs have been implicated as antigens stimulating autoimmunity in atherogenesis (40
). In addition, bacterial HSP 60, like another microbial product such as LPS, may activate the innate immune system (42
). The findings of this study suggest a new function for chlamydial and also human HSP 60: the activation of intrinsic human vascular cells. The HSPs markedly increased E-selectin and ICAM-1 levels on endothelial cells and VCAM-1 to a much lesser extent. In contrast, on SMCs HSPs augmented neither ICAM-1 nor VCAM-1 expression. These distinct patterns may reflect differences in culture conditions between HUVECs and SMCs. However, IL-6 increased in all cell types (HUVECs, SMCs, and monocyte-derived macrophages). Therefore, the differences in the regulation of adhesion molecule expression may also reflect cell type–specific control mechanisms. In either case, the expression of adhesion molecules by the endothelium likely contributes to leukocyte recruitment during atherogenesis, while the function of these molecules in smooth muscle cells remains unclear (17
HSPs (or chaperonins) are generally considered to act intracellularly to preserve cellular protein stability in response to conditions such as heat shock, nutrient deprivation, infections, and inflammatory reactions (44
). Our findings have particular interest, as they delineate a new possible function for this class of proteins, particularly HSP 60. The ability of either chlamydial or human HSP 60 to activate human vascular cells and to trigger NF-κB activation suggests a novel amplification loop in arterial inflammation. Chronic, persistent C. pneumoniae
infection could provoke the expression of both chlamydial and human HSP 60s in the arterial wall. Both of these proteins could then amplify the ongoing inflammatory process, through their actions on human vascular cells described here.
Because HSPs usually localize within cells, they require release into the extracellular space to activate vascular cells. In this regard, it is well known that Chlamydiae, during their life cycle, undergo both phases of chronic, persistent, nonlytic infection, in which they remain viable, but do not replicate, and phases of lytic infection (15
). During these lytic phases, the host cells release both their own HSP 60, produced during the previous chronic phase of infection, and also the human HSP 60, which has been produced in the host cell in response to the infection and to previous noninfectious stimuli (44
), and which we and others have shown in human atheroma (10
). In addition, several observations support the occurrence of cell death within atheroma (45
), providing another pathway for release of HSPs from cells.
In conclusion, this study demonstrates that either chlamydial or human HSP 60 activates human vascular cell functions relevant to atherogenesis and lesional complications. These findings contribute to our understanding of the molecular mechanisms by which a chronic asymptomatic chlamydial infection might influence atherogenesis and trigger acute events.