A Biomimetic Membrane System to Dissect the Role of TNF-α in Inflammatory Disease

The tumor necrosis factor alpha (TNF-α) and its receptor play a critical role in the pathogenesis of autoimmune and/or systemic inflammatory diseases, such as rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis, and Chron’s disease. As a result, TNF- blockade is currently being explored as a treatment strategy to alter the course of these disease states. Despite some promising results, there is considerable variation in regards to efficacy and side effects. For example, only 60% of RA patients respond to TNF-blockers. Likely, this variability is related to the many unanswered fundamental questions regarding the mechanism of TNF-α signaling. One of which is the relationship between the presentation of TNF-α and the corresponding cellular response. The particular questions that this experimental project tries to answer in the context of the response of RA synovial fibroblasts (Figure 1), the so-called conductors of joint destruction, are: How is cellular response such as cytokine secretion and mRNA expression dependent on the concentration of membrane bound TNF-α? How is this response dependent on the ratio of soluble to membrane bound TNF-α? What kind of dynamic reorganization does the TNF-α receptor undergo upon binding? What effects do specific kind and quantities of TNFblocker have on the cellular responses?