Tumour Necrosis Factor Receptor Associated Factor 2 (TRAF2), as one of the important components of NFkB and MAPK signalling in TNF receptor family signalling, has a crucial role in regulating innate and adaptive immunity. TRAF2 has been also implicated in development of some cancers due to its well known anti apoptotic feature. However, definite role of TRAF2 in TNF receptor signalling complex is still controversial and recently It has been reported that Sphingosine-1-phosphate (S1P) is also an essential cofactor for TRAF2 and both are essential for TNF signalling. Since TRAF2 Knock out mice are lethal early after birth, most of the studies has ben carried out using Mouse Embryonic Fibroblasts (MEFs). Since the role of TNF in initiation and development of skin cancer has been reported, we have established the conditional and tissue specific knock out models in keratinocytes and macrophages as key targets of TNF and examined role of TRAF2 and S1P in primary Keratinocytes and Macrophages as well as in transformed MEFs. Interestingly, loss of TRAF2 in Bone Marrow Drive Macrophages (BMDMs) did not cause any defect in TNF-induced NFkB or MAPK activation . Nevertheless, delayed in TNF signalling has been detected in MEFs thereby cause sensitivity of these cells to TNF-induced death. Surprisingly, severe inflammation and dermatitis has been observed in the mice lacking TRAF2 in their keratinocytes suggesting the important role of TRAF2 in regulation of inflammation in skin. In addition, we have investigated the role of S1P in TNF signalling and shown that S1P is dispensable in TNF –induced NFkB, MAPK or cell death.