There is little doubt that inflammation plays a major role in atherosclerosis. As mediators of inflammation, cytokines released from T lymphocytes have the ability to determine the inflammatory phenotype of the host. Although the prototypic pro-inflammatory cytokine, interferon-y has been implicated in atherosclerosis the role of the prototypic anti-inflammatory cytokines interleukin (IL) 4 and 10 is not as clear. The objective of this proposal is to determine the participation of IL4 and IL10 signaling in the atherogenic process by examining their effects on inflammation, macrophage recruitment and lesion morphology.
In aim 1 mice deficient in IL4 and IL10 receptors (IL4R and IL10R) will be crossed onto the atherosclerosis-prone LDLR-/- mice to assess how the loss of signaling by these cytokine affects atherosclerosis. Because IL4R and IL10R are expressed on all cell types in the lesion, studies with mice lacking these receptors will determine the relative importance of the cytokine action on leukocytes versus other cell types in the lesion. Studies in aim 2 are designed to examine the expression of IL4 and IL10 in the local environment of the lesion. Using a macrophage-specific promoter, IL4 and IL10 overexpressing transgenic mice will be generated and used as bone marrow donor mice. The resulting chimeric LDLR-/- mice with macrophages overexpressing IL4 or IL10 in the lesion will provide valuable information on whether the presence of cytokines in the lesion environment can suppress inflammation and reduce lesion formation.
Aim 3 will examine the influence of IL4 and IL10 signaling on well established functions of macrophages as they relate to atherogenesis. First, the ability of IL4 and IL10 to mediate macrophage recruitment to the lesions will be tested by in vitro cell adhesion as well as in vivo cell migration assays. In addition, IL4 and ILIO's influence on extracellular matrix (ECM) remodeling will be examined by first measuring the role of these cytokines in synthesis of matrix metalloproteinases (MMP) by the macrophages, and second, by examining the lesion morphology in atherosclerotic animals with no IL4 or IL10 signaling capability. Measurements of ECM protein deposition, MMP expression and cell infiltration will reveal the participation of these two cytokines in lesion progression. These studies will highlight the importance of inflammation in atherosclerosis and may lead to development of new therapeutic measures targeting inflammation to reduce atherogenesis.
Showing the most recent 10 out of 16 publications
