| Diabetes mellitus is a chronic metabolic disease that is the seventh leading cause of death in the United States. Major complications of diabetes include neuropathy, nephropathy and retinopathy. Clinically these complications are evident as myocardial infarction, angina, blindness, defective nerve conduction, impaired wound healing, and congestive heart failure. Evidence indicates that a link exists between the degree of blood glucose control and the severity of these complications. Despite this, current therapies intended to increase glycemic control in diabetics are not effective in preventing the ultimate progression of these complications. Significant data exists which indicates that protein kinase C (PKC) can be activated as the results of hyperglycemia either by de novo production of diacylglycerol or in response to advanced glycation end-products (AGE). This supports an overarching hypothesis that aberrant protein kinase C function is the central mediator of altered cell function and cellular damage found in diabetes.; Important to many aspects of these diabetic complications is the function of the monocyte. Indeed the macrophage, an immediate descendent of the blood monocyte, is present in areas of acute inflammation such as the atherosclerotic lesion. Activation of PKC is recognized as a consequence of high blood glucose and has been demonstrated in the monocyte. Unfortunately the exact consequences of this aberrant PKC activation in the monocytic model is poorly understood. Consequently a study of monocytic maturation within the context of PKC activation will further our understanding of diabetes immune dysfunction.; The data in this thesis indicate one, that the removal of the tyrosine phosphatase CD45 enhances activation of protein kinase C delta (PKCδ), and two, PKCδ activity in conjunction with STAT6 regulate the expression of the co-stimulatory marker B7.2 (CD86) and three, the expression of CD86 and the production of cytokines in phorbol-12-myristate-13-acetate (PMA)-stimulated promyelocytes is regulated by calcium calmodulin kinase kinase α. These data together indicate that promyelocyte differentiation is a process that is dependent on the activity of PKCδ. Furthermore, this process is subject to regulation by interlukin-4 induced STAT6 activation and CaMKKα. In conclusion we have identified possible targets for future therapies in the treatment of diabetes induced altered immunity. |
