TNF Proteins

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TNF Proteins

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TNF Proteins Background

Tumor necrosis factor (TNF) is a pro-inflammatory cytokine that is also recognized as a neuromodulator. TNF is produced by numerous cell types, including macrophages, monocytes, neurons, fibroblasts, and epithelial cells. This cytokine is involved in normal physiology as well as the pathophysiology of numerous diseases. TNF is pleiotropic, meaning that it has a wide range of cellular effects that are either beneficial or cytotoxic depending on the concentration. At constitutive low levels, it is a neuromodulator in the development of the central nervous system, and is important in the process of regeneration or protection. A higher concentration of TNF has been noted to be involved in various neurological disorders, as well as in diseases of demyelination and degeneration. Therapeutic strategies aimed at decreasing TNF levels systemically have proven ineffective for numerous neurological disorders. Since TNF has profound systemic effects, it may be imperative to specifically block TNF at brain site(s) where neurological dysfunction occurs. Therefore, targeting brain TNF to decrease local levels may provide relief to patients suffering from various disorders known to involve a neural component such as neuropathic pain, depression, Alzheimer’s disease and stroke.

TNF has been implicated in the pathogenesis of numerous diseases, one of which is neuropathic pain. Previous studies in our lab have reported that TNF plays a role in the development and maintenance of neuropathic pain. Studies from our laboratory showed that when brain TNF levels are elevated during neuropathic pain, brain norepinephrine (NE) release is decreased. While TNF has been shown to act as a neuromodulator by inhibiting NE release, the inhibition of NE release when TNF levels are increased is much greater. Administration of antidepressants drugs to naïve animals and to rats experiencing neuropathic pain has been shown to reduce TNF expression in neurons in specific regions of the brain. In animals experiencing sciatic nerve chronic constriction injury, tricyclic antidepressants also alleviated neuropathic pain. In a study using a mouse model of diabetic neuropathy, systemic levels of TNF were increased. When the elevated TNF levels were blocked with a TNF antibody given systemically, diabetic neuropathic pain was alleviated for several weeks. Another study that assessed the role of TNF in chronic diabetic neuropathy showed that in vivo production of TNF is increased under chronic hyperglycemia conditions. Studies from our laboratory using a rat model of diabetic neuropathy showed that levels of TNF increased in specific brain regions, and selectively decreasing these enhanced brain levels prevented pain behaviors associated with diabetic neuropathy.

Higher levels of TNF are also implicated in the pathogenesis of depression. Anxiety and stress, which often precedes the development of and can exacerbate depression, have been shown to activate the pro-inflammatory cytokine cascade, thereby increasing the production of TNF, which is the first cytokine to appear in the cascade. It is interesting that many inflammatory diseases, such as rheumatoid arthritis or infections, are linked to higher rates of Major Depressive Disorder.

It has been reported that serum TNF levels rise in depressed individuals, and it has been shown that antidepressant treatment decreases serum TNF levels.


The TNFR superfamily

The tumor necrosis factor superfamily is a family of ~19 structurally related cytokines that carry out cell signaling by binding to one or more of the ~29 members of the TNF receptor (TNFR) superfamily. TNFs share a high degree of structural homology, but variable sequence, which allows them to target receptors with high affinity and specificity. TNFRs are type-I transmembrane proteins that mediate signal transduction for a wide range of processes including apoptosis, inflammation, cell survival, and lymphoid development. Commensurate with their role in normal signaling, TNFRs have also been implicated in a number of ailments, especially inflammatory diseases, infections, and cancer.

The unifying feature of the TNFR superfamily is an extracellular domain (ECD) consisting of 2 or more cysteine-rich domains (CRDs), which is responsible for binding to protein ligands. Each CRD is held together by pairs of disulfide linked cysteines, which ascend the elongated TNFR structure like rungs of a ladder. CRDs are numbered from the N-terminus so that CRD1 is the furthest from the membrane followed by CRD2, CRD3, and so on, leading to the transmembrane domain, a single-pass α-helix that joins the ECD to the cytosolic domain. The presence of a death domain further classifies certain TNFRs as death receptors, although they do not necessarily mediate cell death. The death domain is a cytosolic region of approximately 80 residues that recruits intracellular adapter proteins through their own death domains upon receptor activation to transduce further downstream signaling. Another group of TNFRs, named decoy receptors, are either secreted or membrane anchored and do not contain functional cytosolic domains. These modulate TNFR signaling by sequestering free ligand. The remaining members of the TNFR superfamily mediate signaling, though not through death domain interactions.

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