TNF-α is a type II transmembrane protein with an intracellular N terminus. It has signalling potential both as a membrane-integrated protein and as a soluble cytokine released after proteolytic cleavage; its soluble form being a non-covalently bound trimer of 17 kDa components. There are two TNF receptors, TNFRI, which is found on most cells in the body, and TNFRII, which is primarily expressed on haemopoietic cells. TNFRI is activated by soluble ligand, TNFRII mainly by the membrane-integrated form. TNF receptors are also shed and act as soluble TNFbinding proteins, inhibiting TNF-α bioactivity by competing with cell surface receptors for free ligand. Ligand binding to TNFR1 induces a range of inflammatory mediators and growth factors via activation of the AP-1 transcription factors or IKβ kinases that, in turn, activate NF-κB. NF-κB activation also importantly induces negative regulators of apoptosis such as c-FLIPL, Bcl-2 and superoxide dismutase. 
If NF-κB activation is not successful then apoptosis is mediated through caspase 8 and, via accumulation of intracellular reactive oxygen, sustained Jun N-terminal kinase activation and mitochondrial pathways. Ligand binding to TNFRII leads to activation of NF-κB, JNK, p38 MAPK, ERK and PI3K pathways, but the biological role of this receptor is still not fully understood. Many pathological situations, including cancer, are characterised by an imbalance between survival and apoptosis signals, but TNF-α is also critical to cellular communication during host defence, inflammation and organogenesis.

References

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