47: TRAF2 regulates NFkB transcription factors to inhibit cell death and inflammation in the skin

Abstract

Tumor Necrosis Factor (TNF) is an important factor in initiation and development of inflammation, and anti TNF therapy is well established for treatment of inflammatory diseases such as psoriasis, rheumatoid arthritis and Crohn’s disease.1 However, anti TNF drugs are not always efficient and developing new effective anti-inflammatory drugs is in the interest of many pharmaceutical companies.1 Therefore, We think that better understanding of TNF signalling pathway helps to discover new targets and design more effective drugs for inflammatory diseases. We have previously showed that Lymphotoxin? signals similar to TNF and suggested to be an alternative factor to induce inflammation in the absent of TNF 2 and both TNF and Lymphotoxin are not blockable by newly proposed inhibitor called Progranulin 3. These results encouraged us to investigate downstream regulator of TNF signalling pathway. Surprisingly, after 30 years of research on TNF, role of many components of TNF pathway are still unclear. TNF Receptor Associated Factor-2 (TRAF2) is one of those molecules which its role is controversial and not well defined yet 4. Since TRAF2 knock-out mice are lethal at birth, we have established various conditional and tissue specific TRAF2 knock-out to study the role of TRAF2 in different tissues. Interestingly, we found that loss of TRAF2 in keratinocytes disrupts TNF signalling and causes cell death, epidermal hyperplasia and skin inflammation. Surprisingly and contradictory to other models, additional loss of TNF did not completely rescue this phonotype. We have found that constitutive activation of non-canonical NF κ B and excessive production of TNF and other cytokines are responsible for this TNF independent inflammation. We propose that this novel model of skin inflammation could be a better model and targeting non-canonical NF κ B signalling might be a more effective target for treatment of inflammatory diseases.