Tumor Necrosis Factor (TNF)

See also TNF-alpha

TNF is widely regarded as one of the most important of the vast array of known cytokines. It was a originally isolated as having an activity that induces necrosis in tumors. TNF is a cytokine produced by many cell types, including macrophages, monocytes, lymphoid cells and fibroblasts in response to inflammation, infection, and other environmental challenges. Isolation of TNF-alpha and beta laid the foundation for the isolation and identification of the a larger family of cytokines, now known as the the TNF superfamily.

What Does TNF Do?

TNF elicits a wide spectrum of cellular responses, including fever, shock, tissue injury, tumor necrosis, anorexia, induction of other cytokines and immunoregulatory molecules, cell proliferation, differentation and apoptosis. As can be imagined, modulation of TNF signaling is a very important therapeutic strategy. For example, the FDA has recently approved new TNF antagonists for the treatment of rheumatoid arthritis.

TNFα has the ability to activate both T cells and DCs.

TNF-alpha

TNF-beta

TNFβ promotes the phagocytic activity of macrophages and neutrophils.

Signal Transduction Through TNF

The responses to TNF are elicited by TNF-induced trimerization of two distinct cell surface receptors, TNFR1 and TNFR2, at least one of which is present in almost every cell type. The structural similarity between the two TNF receptors is limited to their extracellular domains. Although most of the biological activities of TNF appear to be transduced by TNFR1, many can also be mediated by TNFR2. But TNFR2 is a poor inducer of apoptosis.

Exposure to TNF results in activation of two transcription factors, AP-1 and NF-kB.

Most TNF biological activity is elicited trhough the ubiquitous type 1 TNF receptor (TNFR1). TNF binding promotes associates of adaptor protein TNFR-associated death domain (TRADD), which in turn recruits other proteins such as the serine and threonine protein kinase receptor-interaction protein (RIP) and the adaptor protein TNFR-associated factor 2 (TRAF2). Both TRAF2 and RIP are involved in the activaiton of NF-kB by recruiting the inhibitor of kB(IkB) kinase (IKK). The IKK complex contains a kinase that phosphorylates IkBα, an inhibitory protein of NF-kB that sequesters the transcription factor in the cytoplasm. Phosphorylation triggers ubiquitination and degradation of IkBα which then allows the release, modification, and translocation of NF-kB into the nucleus to activate the transcription of target genes.

The molecular mechanisms that underlie the activaiton of MAPKs by TNF are less well defined.

Activation of TNF

It has been suggested that there is an NF-kB-independent component to LPS activaiton of TNF that can be mediated through known or perhaps not yet characterized binding sties in the TNF promoter.