**3.2. Tumor necrosis factor alpha biologic functions**

TNF have a lot of physiologic multifunction including immune and inflammatory roles and the survival and death of different cells. The main function of cytokine is to attract and activate immune cells to sites of infections and to destroy pathogens, such as bacteria and virus. In this context, TNF stimulate vascular endothelial cells to express adhesion molecules (e.g. selectins and ligands for leukocyte integrins) that allows immune system cells to connect the wall of blood vessels. Additionally, complementing the inflammatory response, TNF induces the production of chemokines that increase the affinity of leukocyte to their ligands, the expression of IL-1 and to activate microbicidal functions of immune system cells. For all TNF importance in the inflammatory reaction, if low quantities of this cytokine are presented in the local, the containment of the infection may be impaired [33, 37, 41–43].

TNF is also well known to act in inflammatory reaction of some autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease. Errors in this production are responsible for a considerable number of autoimmune, neoplastic and other diseases. Under these conditions, the treatment of these diseases are based on biologic agents targeting TNF, and thus looking for reducing the number of available TNF molecules or to block it receptors [33, 35, 40].

TNF also promotes necrosis of tumor cells by inducing programmed cell death, a cytolytic potential. The activation of apoptosis mechanism is mediated by TNFR1, by stimulating the recruitment of death signaling proteins, such as Fas-associated protein with death, TNFR-associated factor (TRAF)-1 and TNFR-associated death domain protein (TRADD). These intracellular proteins are responsible for the release of other proteins such as procaspase-8, which in it activated form activate caspase-3, caspase-6, caspase-7 and other cytosolic substrates. These proteins induce genomic DNA degradation and cell death through interacting with latent DNAse. Evidences also suggest that TNF have the capacity to induce carcinogenesis and to stabilize tumors, an event that it is opposite of the previous explained, by DNA mutations and it mechanism of repair (i.e. genotoxic potential). This is possible due to the activation of NF-κB in tumor cells and by promoting production of IL-6 (a tumor-promoting cytokine), both facilitate metastasis and cancer cells to escape from immune system defense [35, 40–42].

There are other biological events and actions caused by TNF. When this cytokine is produced in large scale, such as in severe infection, it may induce shock or decrease of blood pressure due to reducing vascular muscle tone and myocardial contractility. Additionally, in high concentrations TNF can reduce blood glucose concentration, and cause intravascular thrombosis (by decreasing anticoagulant capabilities of the endothelium). TNF is also known as an endogenous pyrogen because it promotes fever by stimulating hypothalamus cells to produce prostaglandins [33, 40].
