Attenuation of Inflammation by the NF-kappaB Member RelB

Inflammation is an intricate physiological process designed to protect host tissues from the harmful effects of irritants and pathogens. However, excessive and/or prolonged inflammation can result in severe tissue damage and loss of function. Fibroblasts, in addition to their role as key structural cells, are also integral to inciting and promoting inflammatory responses. Fibroblasts produce many proinflammatory mediators such as interleukin-6 (IL-6), interleukin-8 (IL-8) and prostaglandin E2 (PGE2) following exposure to provoking stimuli. Inflammation is also heavily reliant on NF-kappaB, a family of cytosolic transcription factors expressed ubiquitously throughout the body, which drives expression of many proinflammatory mediators. Interestingly, the NF-kappaB member RelB has anti-inflammatory properties. For example, RelB-deficient mice exhibit severe multi-organ inflammation characterized by excessive proinflammatory mediator production. We hypothesized that RelB is a critical attenuator of inflammatory mediator production in host structural cells, namely fibroblasts. Further, RelB may have significant potential as a next-generation anti-inflammatory agent. To test our hypothesis and reveal the anti-inflammatory nature of RelB, RelB was transiently overexpressed in the lungs of mice via intranasal delivery of a recombinant adenovirus. A regimen of cigarette smoke was subsequently given to these mice to induce lung inflammation. Intriguingly, cigarette smoke-induced inflammatory mediator production and proinflammatory cell migration into the lungs were significantly attenuated in the lungs of RelB-treated mice compared to control groups. Next, the anti-inflammatory potential of RelB was tested in an in vitro model utilizing primary human lung fibroblasts. Interleukin-1β; (IL-1β)-induced inflammatory mediator production was significantly attenuated in these cells following RelB overexpression. Further experiments indicated that RelB may regulate inflammatory mediator production in fibroblasts in part through a mechanism involving microRNA-146a (miR-146a). Lastly, the IL-1β-induced inflammatory responses of fibroblasts derived from three distinct ocular tissues were analyzed for susceptibility to RelB anti-inflammatory effects. RelB overexpression reduced cyclooxygenase-2 (Cox-2) expression and IL-6 production in these cells, demonstrating the effectiveness of RelB in attenuating inflammatory mediator production in ocular fibroblasts. The findings documented in this thesis underscore the therapeutic potential of RelB. Future strategies increasing RelB expression may be beneficial to the treatment of human inflammatory diseases.