IKKBETA LINKS MACROPHAGE INFLAMMATION TO OBESITY-INDUCED ATHEROSCLEROSIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Obesity is associated with several diseases. Inflammation is a common link between obesity and associated diseases. Two such diseases influencing the obese population are diabetes in the form of insulin resistance, and coronary artery disease in the form of atherosclerosis. Both of these obesity-induced complications are associated with inflammation in either the blood vessel wall (atherosclerosis) or in adipose tissue (insulin resistance). Many inflammatory pathways that contribute to atherosclerosis initiation and development are regulated by transcriptional factor nuclear factor-¿B (NF-¿B), a central coordinator of the innate and adaptive immune responses (8, 9). NF-¿B is rapidly activated in response to various stimuli, including cytokines, infectious agents and reactive oxygen species (10). I¿B kinase ¿ (IKK¿) is the predominant catalytic subunit of the IKK complex that is required for activation of NF-¿B by inflammatory mediators such as TNF¿ and IL-1s in the canonical or classical activation pathway (11, 12). In the past decade, IKK¿ has been established as a critical molecular link between inflammation and pathogenesis of several chronic diseases such as cancer. However, the role of IKK¿ in atherosclerosis has not been thoroughly investigated. IKK¿ activation has been detected in atherosclerosis and in vascular inflammatory reactions in animal models and humans (13-15). Despite the strong evidence suggesting the involvement of IKK¿ activation in atherosclerosis progression, the role of IKK¿-mediated inflammatory functions by macrophages in atherosclerosis remain unclear. The previous studies using various mouse models have given inconsistent results and further research is urgently needed to define the role of macrophage IKK¿ in atherosclerosis. Preliminary data demonstrate that deficiency of IKKbeta in macrophages promotes inflammation. In addition, pilot studies indicate that deficiency of IKKbeta in macrophages reduces diet-induced atherosclerosis. We hypothesize that IKKbeta plays an important role linking macrophage inflammation to obesity-induced atherosclerosis and insulin resistance. Studies will address the role of macrophage IKKbeta in experimental models of diet-induced atherosclerosis and insulin resistance.