Macrophages are activated to produce inflammatory cytokines in response to a variety of external stimuli. Some of the most potent of these stimuli are lipids derived from the cell ways of infectious organisms. These lipids activate cell surface receptors than then engage downstream signaling pathways responsible for the induction of cytokine expression gene expression. One of the best characterized of the receptor signaling pathways involves lipopolysaccharide binding protein (LBP) and CD14, a 55 kDa glycosyl phosphatidylinositol (GPI)-linked protein that is also present in a soluble form (sCD14) in serum. CD14 binds lipopolysaccharides, presented to it by LBP, that are derived from the outermost layer of Gram-negative bacteria and activates a signaling cascade via a newly described family of protein called Toll receptors (TLRs). This results in the production of tumor necrosis-alpha (TNF- alpha) interleukin-6 (IL-6), and interleukin-1(IL-1), major cytokine effectors of the inflammatory response. This CD14 initiated response has been shown to be important in the pathogenesis of septic shock following Gram-negative septicemia. Another Gram negative bacteria. Chlamydia pneumoniae, has recently been implicated in the progression of an another important medical disease, atherosclerosis. Chlamydia is an obligate intracellular parasite that resides within macrophages and recent data has suggested that the lipopolysaccharides from Chlamydia may play a role in accelerating atherosclerotic plaque development by enhancing the formation of the macrophage foam cell, the histologic hallmark of the early atheroma. In the previous grant award period, we generated animals lacking the CD14 receptor and LBP. Macrophages taken from these animals will be used to explore the role of Chlamydia and its lipopolysaccharide coat in infecting and activating macrophages. As mouse models of atherosclerosis can be used to study the progression of lesions in animals infected with Chlamydial organisms, the CD14 and LBP deficient mice will also be used to perform studies of the relevance of these pathways to atherogenesis in vivo. Comparisons will be made of the Chlamydial activating signaling pathways in macrophages to those pathways engaged by enteric Gram negative pathogens in order to analyze the roles of CD14, LBP, and TLRs in these differing infection. These studies should provide new insights into the biology of Chlamydia- induced atherosclerotic lesion progression as well as more detailed understanding of macrophage activation by infectious agents and their pro-inflammatory cell wall lipids.
Showing the most recent 10 out of 98 publications
