TNF

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. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Upregulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line (PubMed:22517918, PubMed:16829952, PubMed:23396208). Induces insulin resistance in adipocytes via inhibition of insulin-induced IRS1 tyrosine phosphorylation and insulin-induced glucose uptake. Induces GKAP42 protein degradation in adipocytes which is partially responsible for TNF-induced insulin resistance (By similarity). Plays a role in angiogenesis by inducing VEGF production synergistically with IL1B and IL6 (PubMed:12794819).

The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.

Involvement in disease

Psoriatic arthritis

PSORAS

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).

None

Disease susceptibility is associated with variants affecting the gene represented in this entry.

Post-translational modifications

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.

O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid.

Sequence similarities

Belongs to the tumor necrosis factor family.

Cellular localization

• Cell membrane
• Single-pass type II membrane protein
• Tumor necrosis factor, membrane form
• Membrane
• Single-pass type II membrane protein
• Tumor necrosis factor, soluble form
• Secreted
• C-domain 1
• Secreted
• C-domain 2
• Secreted

Alternative names

• Tumor necrosis factor
• Cachectin
• TNF-alpha
• Tumor necrosis factor ligand superfamily member 2
• TNF-a
• TNF
• TNFA
• TNFSF2

Database links

• entrezGene:7124
• omim:191160
• swissprot:P01375

Target type

Proteins

Primary research area

Immunology & Infectious Disease

Other research areas

• Cardiovascular
• Immuno-oncology
• Neuroscience
• Oncology

Molecular weight

25644Da