Abstract
Since its discovery in 1975, TNFα has been a subject of intense study as it plays significant roles in both immunity and cancer. Such attention is well deserved as TNFα is unique in its engagement of pleiotropic signaling via its two receptors: TNFR1 and TNFR2. Extensive research has yielded mechanistic insights into how a single cytokine can provoke a disparate range of cellular responses, from proliferation and survival to apoptosis and necrosis. Understanding the intracellular signaling pathways induced by this single cytokine via its two receptors is key to further revelation of its exact functions in the many disease states and immune responses in which it plays a role. In this review, we describe the signaling complexes formed by TNFR1 and TNFR2 that lead to each potential cellular response, namely, canonical and non-canonical NF-κB activation, apoptosis and necrosis. This is followed by a discussion of data from in vivo mouse and human studies to examine the differential impacts of TNFR1 versus TNFR2 signaling.
Highlights
Tumor Necrosis Factor alpha (TNFa) is a central mediator in the immunologic processes of infection control, autoimmunity, allergic disease, as well as the anti-neoplastic activity for which it was named
We identify that a greater understanding of this pathway may offer opportunities for novel therapeutic targeting as well as treatment optimization for current TNFa inhibition approaches
Cell death mediated by TNFR2 is a result of crosstalk, where activity of TNFR2 indirectly influences the signaling complexes that can form at TNFR1
Summary
Tumor Necrosis Factor alpha (TNFa) is a central mediator in the immunologic processes of infection control, autoimmunity, allergic disease, as well as the anti-neoplastic activity for which it was named. The particular response of a given cell to activation by TNFa is determined by receptor expression and intracellular conditions, such as ubiquitination of the signaling complex and the availability of caspases.
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