Tumor necrosis factor alpha (TNFα) is the prototypic ligand of the TNF superfamily. TNFα forms a homotrimer and functions by activating two types of receptors TNF-R1 (TNF receptor type 1,p55R) and TNF-R2 (TNF receptor type 2,p75R). TNFα is a pleiotropic cytokine that is capable to promote inflammation, to induce apoptotic cell death, and to inhibit tumorigenesis and viral replication. TNFα is a potent lymphoid factor that exerts cytotoxic effects on a wide range of tumor cells and certain other target cells.
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.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.Plays a role in angiogenesis by inducing VEGF production synergistically with IL1B and IL6.
CD137 (also known as 4-1BB) is a surface co-stimulatory glycoprotein originally described as present on activated T lymphocytes , which belongs to the tumor necrosis factor (TNF) receptor superfamily. It is expressed mainly on activated CD4+ and CD8+ T cells , and binds to a high-affinity ligand (4-1BBL) expressed on several antigen-presenting cells such as macrophages and activated B cells. Upon ligand binding , 4-1BB is associated with the tumor necrosis factor receptor–associated factors (TRAFs) , the adaptor protein which mediates downstream signaling events including the activation of NF-kappaB and cytokine production. 4-1BB signaling either by binding to 4-1BBL or by antibody ligation delivers signals for T-cell activation and growth , as well as monocyte proliferation and B-cell survival , and plays an important role in the amplification of T cell-mediated immune responses. In addition , CD137 and CD137L are expressed in different Human primary tumor tissues , suggesting that they may influence the progression of tumors. Crosslinking of CD137 on activated T cells has shown promise in enhancing anti-tumor immune responses in murine models , and agonistic anti-CD137 antibodies are currently being tested in phase I clinical trials. Soluble forms of CD137 (sCD137) are generated by differential splicing. sCD137 can bind to CD137 ligand to antagonize the costimulatory activities of the membrane-bound CD137 and reduce T cell proliferation and IL-2 secretion.
SerpinA1, also known as Alpha-1 antitrypsin (AAT), is a prototype member of the Serpin superfamily of the serine protease inhibitors. This serine protease inhibitor blocks the protease, neutrophil elastase. Alpha-1 antitrypsin is mainly produced in the liver and acts as an antiprotease. Its principal function is to inactivate neutrophil elastase, preventing tissue damage. SerpinA1, an acute phase protein and the classical neutrophil elastase inhibitor, is localized within lipid rafts in primary human monocytes in vitro. It association with monocytes is inhibited by cholesterol depleting/efflux-stimulating agents and oxidized low-density lipoprotein (oxLDL) and conversely, enhanced by free cholesterol. Furthermore, SerpinA1/monocyte association per se depletes lipid raft cholesterol as characterized by the activation of extracellular signal-regulated kinase 2, formation of cytosolic lipid droplets, and a complete inhibition of oxLDL uptake by monocytes. Alpha-1 antitrypsin deficiency is a recently identified genetic disease that occurs almost as frequently as cystic fibrosis. It is caused by various mutations in the SerpinA1 gene, and has numerous clinical implications. Alpha-1 antitrypsin deficiency is an inherited disease affecting the lung and liver. In the liver, alpha-1 antitrypsin deficiency may manifest as benign neonatal hepatitis syndrome, a small percentage of adults develop liver fibrosis, with progression to cirrhosis and hepatocellular carcinoma.
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