TNF once held much promise as a cancer chemotherapeutic, however toxicity limits its clinical utility. Therapeutic manipulation of the TNF signalling pathway may be an effective alternative whilst circumventing toxicity. However, cell-to-cell differences in TNF signalling are becoming increasingly apparent and there is significant disagreement over the role of key TNF receptor 1 (TNFR1) signalling components. Clarification if this will facilitate realisation of the therapeutic potential of targeting the TNF pathway.
TRAF2 has long been identified as a component of the TNFR1 although its function is controversial. It has been suggested that TRAF2 E3 ligase activity is essential for activation of the transcription factor NFĸB and MAP kinase signalling through TNFR1. Early post-natal lethality of TRAF2 knock-out mice makes study of this molecule in primary cells difficult, and most research has utilised transformed mouse embryonic fibroblasts.
We revisited the role of TRAF2 in TNF signalling using tissue specific knock out mice. We found TRAF2 regulates TNF mediated canonical NFĸB and MAP kinase signalling and inhibit cell death in keratinocytes and that its deletion causes epidermal hyperplasia and skin inflammation.
However, deletion of TNF only delays the inflammation in keratinocytes specific TRAF2 knock out, suggesting an additional role of TRAF2 in regulating skin homeostasis. We have found out that TRAF2 regulates non canonical NFĸB signalling and that loss of it causes constitutive activation of that pathway.
These data suggest TRAF2 regulates canonical and non canonical NFĸB pathways to inhibit cell death and inflammation. These findings may have implications for future therapeutic targeting of the TNF pathway in the context of cancer and inflammatory disease.