Product Description
Insulin dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by the selective destruction of pancreatic beta cells. Despite an identified genetic predisposition for the disease, the low concordance rate in monozygotic twins supports environmental factors such as virus infection in the development of diabetes. EMCV has been used at low doses in genetically susceptible mice to initiate the disease and this has been a useful tool to understand the role of macrophages in diabetes development. EMCV-induced IDDM appears to be mediated by macrophage production of soluble mediators such as nitric oxide, IL-1 and TNF. However, the mechanisms by which EMCV stimulate macrophage activation are poorly understood. EMCV elicits the expression of the inflammatory genes inducible nitric oxide synthase (iNOS), interleukin 1 (IL-1), and cyclooxygenase-2 (COX-2), and the expression of each of these genes is dependent upon the activation of NF-kappaB as well as the activation of a secondary signaling pathway for each gene; iPLA2 for iNOS, ERK for IL-1, and p38 and JNK for COX-2. The purpose of this study was to identify the upstream activator(s) of these signaling cascades in macrophages in response to viral infection. To this end, we have identified the chemokine receptor Ccr5 as playing an integral role in initiating pro-inflammatory signaling events following EMCV infection, and present evidence that the initiation of signaling is through the G-proteins coupled to Ccr5.
