A role for NF-kappa B in inflammation and autoimmunity.

摘要

NF-kappaB is a transcription factor which plays a role in many immune and inflammatory processes. Tight control of NF-kappaB activity is essential and dysregulation of NF-kappaB has been associated with a number of immune and inflammatory diseases. This dissertation further explores the role of NF-kappaB in inflammation and in autoimmune diabetes.; NF-kappaB and inflammation. Cyclooxygenase-2 (COX-2) plays a major role in inflammatory processes and its inducible expression has been correlated with several diseases, such as inflammatory bowel disease and colorectal cancer. COX-2 expression occurs rapidly after stimulation with cytokines, growth factors, and endotoxin. Because these stimuli upregulate COX-2 expression, COX-2 has been viewed primarily as a pro-inflammatory enzyme. However, recent evidence suggests that COX-2 can function in both a pro- and anti-inflammatory manner. I hypothesized that these properties of COX-2 could be due to the opposing actions of COX-2 on NF-kappaB activation. I found that COX-2 and its effector prostaglandins (PGs) can both upregulate and downregulate NF-kappaB function. Furthermore, one key PG, PGE2, upregulates NF-kappaB activity without increasing nuclear levels, but instead through enhancement of the NF-kappaB transactivation domain (TAD).; NF-kappaB and autoimmunity. Dendritic cells (DCs) are antigen presenting cells (APC) involved in mediating T cell immunity. I found that DCs prepared from nonobese diabetic (NOD) mice, a model for autoimmune diabetes, exhibit an enhanced APC function. Specifically, NOD DCs are more sensitive to stimulation by TNFalpha, LPS, alphaCD40 Ab, and IL-12 as compared to DCs prepared from control strains, resulting in increased levels of IL-12 and TNFalpha secretion and an enhanced capacity to stimulate naive T cells. The elevated APC function of NOD DCs is associated with increased activation of NF-kappaB. Importantly, transfection of NOD DCs with a modified form of IkappaBalpha, which inhibits NF-kappaB activity, significantly reduces the level of IL-12 secretion and the capacity of DCs to stimulate T cells. These results provide direct evidence that NF-kappaB plays a key role in regulating the APC function of DCs. Furthermore, dysregulation of NF-kappaB and concomitantly increased APC function by DCs may contribute to the T cell mediated autoimmunity observed in NOD mice.