Autoimmunity Excessive production of TNF plays a key role in the pathology of
autoimmune diseases, such as
rheumatoid arthritis,
inflammatory bowel disease,
psoriatic arthritis,
psoriasis, and
noninfectious uveitis. In these diseases, TNF is erroneously secreted by immune cells in response to environmental factors or genetic mutations. TNF then triggers an inflammatory response, damaging normal tissue.
TNF blockers, which prevent TNF from binding to its receptors, are often used to treat these diseases. In some cancers, TNF has been shown to play an inhibitory role, primarily when injected locally, repeatedly, and at high concentrations. Due to TNF's adverse side effects, potential TNF cancer treatments seek to maximize cytotoxicity to tumors while minimizing exposure to the entire body. Some treatments increase cytotoxicity by inhibiting the cell survival pathways of tumors before treatment with TNF. Other treatments localize TNF activity using antibody-TNF fusions, also known as
immunocytokines. Local TNF treatment has been shown to induce tumor regression, though they rarely induce complete
remission. Body-wide administration of TNF has shown low efficacy and high side effects. Conversely, TNF plays a role in the progression of
HIV by inducing apoptosis of
T cells in HIV-infected people. TNF blockage has reportedly led to clinical improvement in HIV without worsening the infection, though data is limited. Although TNF blockers showed efficacy in treating sepsis in mice, they showed mixed results in treating sepsis in humans. This is believed to be due to the dual role that TNF plays in the immune system; blocking TNF reduces the severe inflammation that causes sepsis, but also hinders the immune system's ability to resist the infection. It is hypothesized that TNF blockers are more beneficial in cases of severe sepsis, where the probability of death is higher. Despite this connection, TNF blockers are not used to treat liver fibrosis. In clinical trials of alcoholic hepatitis, TNF blockers had no significant effect.
Nonalcoholic fatty liver disease TNF plays a key role in
nonalcoholic fatty liver disease (NAFLD), in which fat builds up in the liver, leading to injury, inflammation, and scarring. TNF promotes insulin resistance, which promotes fat build up in the liver. As fat builds up in the liver and surrounding adipose tissue, immune cells may infiltrate the expanding tissue and secrete TNF, causing inflammation. Thus, TNF may serve as a causal link between inflammation, insulin resistance, and fat accumulation in the liver. Clinical studies have shown that TNF levels are correlated with the severity of NAFLD, although some studies have shown otherwise. Pharmacological strategies that downregulate TNF have shown favorable effects on NAFLD, while the efficacy of TNF blockers is yet to be evaluated.
Muscle wasting Conditions that cause inflammation, such as cancer, can elevate TNF levels, which contributes to
muscle wasting. TNF contributes to muscle wasting by activating the NF-κB pathway, which activates the
ubiquitin–proteasome pathway to degrade protein, and by inhibiting the activation of
satellite cells, which are responsible for protein regeneration. However, TNF blockers have had limited effect on muscle wasting in clinical studies, likely due to the multifactorial nature of muscle wasting.
Exercise During exercise, the level of
IL-6, a TNF inhibitor, rapidly increases, leading to an anti-inflammatory effect. This is followed by a subsequent increase in the levels of
IL-10 and soluble TNF receptors, both of which also inhibit TNF. While moderate exercise does not increase TNF levels, strenuous exercise has been shown to increase TNF levels two-fold, causing a pro-inflammatory effect. However, this proinflammatory effect is outweighed by the anti-inflammatory effect of IL-6, which can increase 50-fold. Regular exercise has been shown to reduce base TNF levels in the long term. Thus, exercise is generally considered to inhibit TNF, which contributes to the overall anti-inflammatory effect of exercise.
Neuroinflammation In the
central nervous system, TNF is primarily produced by
microglia, a type of macrophage, but also by
neurons,
endothelial cells, and immune cells. Excessive TNF contributes to
neuroinflammation by causing
excitotoxic neuronal cell death, increasing
glutamate levels, activating microglial cells, and disrupting the
blood–brain barrier. As a result, TNF is seen to play an important role in central nervous system disorders associated with neuroinflammation, including
neurosarcoidosis,
multiple sclerosis,
Neuro-Behçet's disease. Paradoxically, TNF-blockers can cause demyelination of neurons and worsen multiple sclerosis symptoms. This is believed to be due to the homeostatic role of TNF in the central nervous system, especially on neuron myelination via TNFR2. The selective blockade of TNFR1 has shown positive outcomes in animal models.
TRAPS In
TNF receptor associated periodic syndrome (TRAPS), genetic mutations in TNFR1 lead to defective binding of TNFR1 to TNF, as well as defective shedding of TNFR1, a mechanism that attenuates TNFR1 signalling. This causes periodic inflammation, though the exact mechanism is unknown. TNF blockers such as etanercept have shown partial efficacy in reducing symptoms, while other TNF blockers such as
adalimumab and infliximab have been shown to worsen symptoms.
Taste perception Excessive levels of inflammatory cytokines, such as during infection or autoimmunity, have been associated with
anorexia and reduced food intake. It is hypothesized that TNF reduces food intake by increasing sensitivity to bitter taste, though the exact mechanisms of this are unknown. == Pharmacology ==