axis activates mlk2/mlk3 and these kinases phosphorylate mkk7, which then activates jnk. jnk translocates to the nucleus and activates transcription factors such as c-jun and atf2. the jnk pathway is involved in cell differentiation, proliferation, and is generally pro-apoptotic. induction of death signaling: like all death-domain-containing members of the tnfr superfamily, tnfr1 is involved in death signaling. however, tnf-induced cell death plays only a minor role compared to its overwhelming functions in the inflammatory process. its death-inducing capability is weak compared to other family members (such as fas), and often masked by the anti-apoptotic effects of nf-κb. nevertheless, tradd binds fadd, which then recruits the cysteine protease caspase-8. a high concentration of caspase-8 induces its autoproteolytic activation and subsequent cleaving of effector caspases, leading to cell apoptosis. the myriad and often-conflicting effects mediated by the above pathways indicate the existence of extensive cross-talk. for instance, nf-κb enhances the transcription of c-flip, bcl-2, and ciap1 / ciap2, inhibitory proteins that interfere with death signaling. on the other hand, activated caspases cleave several components of the nf-κb pathway, including rip, ikk, and the subunits of nf-κb itself. other factors, such as cell type, concurrent stimulation of other cytokines, or the amount of reactive oxygen species (ros) can shift the balance in favor of one pathway or another. such complicated signaling ensures that, whenever tnf is released, various cells with vastly diverse functions and conditions can all respond appropriately to inflammation. both protein molecules tumor necrosis factor alpha and keratin 17 appear to be related in case of oral submucous fibrosis in animal models tnf selectively kills autoreactive t cells. there is also evidence that tnf-α signaling triggers downstream epigenetic modifications that result in lasting enhancement of pro-inflammatory responses in cells. enzyme regulation this protein may use the morpheein model of allosteric regulation. clinical significance tnf was thought to be produced primarily by macrophages, but it is produced also by a broad variety of cell types including lymphoid cells, mast cells, endothelial cells, cardiac myocytes, adipose tissue, fibroblasts, and neurons. large amounts of tnf are released in response to lipopolysaccharide, other bacterial products, and interleukin-1 (il-1). in the skin, mast cells appear to be the predominant source of pre-formed tnf, which can be released upon inflammatory stimulus (e.g., lps). it has a number of actions on various organ systems, generally together with il-1 and interleukin-6 (il-6): on the hypothalamus: stimulation of the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (crh) suppressing appetite fever on the liver: stimulating the acute phase response, leading to an increase in c-reactive protein and a number of other mediators. it also induces insulin resistance by promoting serine-phosphorylation of insulin receptor substrate-1 (irs-1), which impairs insulin signaling it is a potent chemoattractant for neutrophils, and promotes the expression of adhesion molecules on endothelial cells, helping neutrophils migrate. on macrophages: stimulates phagocytosis, and production of il-1 oxidants and the inflammatory lipid prostaglandin e2 (pge2) on other tissues: increasing insulin resistance. tnf phosphorylates insulin receptor serine residues, blocking signal transduction. on metabolism and food intake: regulates bitter taste perception. a local increase in concentration of tnf will cause the cardinal signs of inflammation to occur: heat, swelling, redness, pain and loss of function. whereas high concentrations of tnf induce shock-like symptoms, the prolonged exposure to low concentrations of tnf can result in cachexia, a wasting syndrome. this can be found, for example, in cancer patients. said et al. showed that tnf causes an il-10-dependent inhibition of cd4 t-cell expansion and function by up-regulating pd-1 levels on monocytes which leads to il-10 production by monocytes after binding of pd-1 by pd-l. the research of pedersen et al. indicates that tnf increase in response to sepsis is inhibited by the exercise-induced production of myokines. to study whether acute exercise induces a true anti-inflammatory response, a model of 'low grade inflammation' was established in which a low dose of e. coli endotoxin was administered to healthy volunteers, who had been randomised to either rest or exercise prior to endotoxin administration. in resting subjects, endotoxin induced a 2- to 3-fold increase in circulating levels of tnf. in contrast, when the subjects performed 3 hours of ergometer cycling and received the endotoxin bolus at 2.5 h, the tnf response was totally blunted. this study provides some evidence that acute exercise may inhibit tnf production. in the brain tnf can protect against excitotoxicity. tnf strengthens synapses. tnf in neurons promotes their survival, whereas tnf in macrophages and microglia results in neurotoxins that induce apoptosis. tnf-α and il-6 concentrations are elevated in obesity. monoclonal antibody against tnf-α is associated with increases rather than decreases in obesity, indicating that inflammation is the result, rather than the cause, of obesity. tnf and il-6 are the most prominent cytokines predicting covid-19 severity and death. pharmacology main article: tnf inhibition tnf promotes the inflammatory response, which, in turn, causes many of the clinical problems associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma. these disorders are sometimes treated by using a tnf inhibitor. this inhibition can be achieved with a monoclonal antibody such as infliximab (remicade) binding directly to tnf, adalimumab (humira), certolizumab pegol (cimzia) or with a decoy circulating receptor fusion protein such as etanercept (enbrel) which binds to tnf with greater affinity than the tnfr. on the other hand, some patients treated with tnf inhibitors develop an aggravation of their disease or new onset of autoimmunity. tnf seems to have an immunosuppressive facet as well. one explanation for a possible mechanism is this observation that tnf has a positive effect on regulatory t cells (tregs), due to its binding to the tumor necrosis factor receptor 2 (tnfr2). anti-tnf therapy has shown only modest effects in cancer therapy. treatment of renal cell carcinoma with infliximab resulted in prolonged disease stabilization in certain patients. etanercept was tested for treating patients with breast cancer and ovarian cancer showing prolonged disease stabilization in certain patients via downregulation of il-6 and ccl2. on the other hand, adding infliximab or etanercept to gemcitabine for treating patients with advanced pancreatic cancer was not associated with differences in efficacy when compared with placebo. interactions tnf has been shown to interact with tnfrsf1a. nomenclature because ltα is no longer referred to as tnfβ, tnfα, as the previous gene symbol, is now simply called tnf, as shown in hgnc (hugo gene nomenclature committee) database.