Tumor necrosis factor alpha (TNF- ), also known as cachectin, is a member of the TNF ligand superfamily and has been designated TNFSF1A. It binds to the same cell surface receptors, and shares some biological functions with TNF- /TNFSF1B. TNF- ?inhibits the growth of certain tumors. It also plays a critical role in normal host resistance to infection, serving as an immunomodulator and as a mediator of inflammatory responses. Over-production of TNF has been implicated in a number of pathological conditions, including cachexia, septic shock, and autoimmune disorders (1 - 4). TNF- ?is produced primarily by activated macrophages (1 - 6). Various other porcine cell types, including NK cells (6), keratinocytes (7), vascular smooth muscle cells (8), and granulosa lutein cells (9) are also known to produce TNF- .
The porcine TNF- ?gene product is a 232 amino acid (aa) residue type II membrane glycoprotein containing a 35 aa cytoplasmic domain, a 21 aa transmembrane domain and a 178 aa extracellular domain (10 - 13). The 156 aa residue soluble TNF- ?is released from the C-terminus of the membrane protein by TNF- ?converting enzyme (TACE, ADAM17), a member of the ADAM (a disintegrin and metalloprotease domain) family of metalloproteases(10, 11, 14). The biologically active TNF- ?has been shown to exist as a trimer (1 - 4). Porcine TNF- ?is active on mouse cells and shares 89% and 79% aa sequence identity with human and mouse TNF- , respectively (10, 14).Two distinct TNF receptors, referred to as type I (type B, p55, or TNFRSF1A) and type II (type A, p75, or TNFRSF1B), that specifically bind TNF- ?and TNF- ?with equal affinities are known (15 - 17). The two TNF receptors share aa sequence homology in their extracellular but not their cytoplasmic domains, suggesting that the two receptors employ different signal transduction pathways. Soluble forms of both types of receptors have been found in human and mouse serum (18 - 20).
These soluble receptors are capable of neutralizing the biological activities of the TNFs and may serve to modulate the activities of TNF.? Porcine TNF RI shares 79% and 72% aa homology with the human and mouse TNF RI, respectively (21 - 23).
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