TNF-alpha Human Active Protein

This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, and cancer. Knockout studies in mice also suggested the neuroprotective function of this cytokine. [provided by RefSeq, Jul 2008]

Function: Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Ref.24The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells. Ref.24

Subunit structure: Homotrimer. Interacts with SPPL2B. Ref.25

Subcellular location: Cell membrane; Single-pass type II membrane protein Ref.24. Tumor necrosis factor, membrane form: Membrane; Single-pass type II membrane protein Ref.24. Tumor necrosis factor, soluble form: Secreted Ref.24. C-domain 1: Secreted Ref.24. C-domain 2: Secreted Ref.24.

Post-translational modification: The soluble form derives from the membrane form by proteolytic processing. The membrane-bound form is further proteolytically processed by SPPL2A or SPPL2B through regulated intramembrane proteolysis producing TNF intracellular domains (ICD1 and ICD2) released in the cytosol and TNF C-domain 1 and C-domain 2 secreted into the extracellular space.The membrane form, but not the soluble form, is phosphorylated on serine residues. Dephosphorylation of the membrane form occurs by binding to soluble TNFRSF1A/TNFR1. Ref.18 Ref.19O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid. Ref.15

Polymorphism: Genetic variations in TNF influence susceptibility to hepatitis B virus (HBV) infection [

MIM:610424].Genetic variations in TNF are involved in susceptibility to malaria [

MIM:611162].

Involvement in disease: Psoriatic arthritis (PSORAS) [MIM:607507]: An inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoid like pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis).Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.

Sequence similarities: Belongs to the tumor necrosis factor family.

Sequence caution: The sequence AAF71992.1 differs from that shown. Reason: Frameshift at positions 91 and 157. The sequence CAA75070.1 differs from that shown. Reason: Erroneous gene model prediction.