Tumor Necrosis Factor-α

Cytokines are low-molecular-weight intercellular signaling molecules.^1-4 Cytokines are produced de novo in response to an immune stimulus. They regulate immune cell homeostasis by mediating innate and acquired immunity, and inflammation in human health and disease. They generally (although not always) act over short distances and short time spans and at very low concentrations. They act by binding to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter its behavior. Responses to cytokines include increasing or decreasing expression of membrane proteins (including cytokine receptors), proliferation and secretion of effector molecules. It is common for different cell types to secrete the same cytokine or for a single cytokine to act on several different cell types (pleiotropy). Cytokines are redundant in their activity, meaning similar functions can be stimulated by different cytokines. Cytokines are often produced in a cascade, as one cytokine stimulates its target cells to make additional cytokines. Cytokines can also act synergistically (two or more cytokines acting together) or antagonistically (cytokines causing opposing activities).

Tumor necrosis factor-alpha (TNF-α) is an important pleiotropic cytokine involved in host defense, inflammation, and apoptosis.³ Local increases in TNF-α concentrations cause the five cardinal signs of inflammation: heat, swelling, redness, pain and loss of function.³ TNF-α was initially identified as a serum factor that could induce the hemorrhagic necrosis of tumors in patients following acute bacterial infections.⁵ TNF-α is a central cytokine in inflammatory reactions, and biologics that neutralize TNF are among the most successful drugs for the treatment of chronic inflammatory and autoimmune pathologies.⁵ In recent years, it became clear that TNF-α drives inflammatory responses not only directly by inducing inflammatory gene expression but also indirectly by inducing cell death, instigating inflammatory immune reactions and disease development.⁵ It plays a double role in regulation of immune responses, acting both as a proinflammatory mediator, initiating a strong inflammatory response, and an immunosuppressive mediator, inhibiting the development of autoimmune diseases and tumorigenesis, and exhibiting a vital role in maintenance of immune homeostasis by limiting the extent and duration of inflammatory processes.³ TNF-α plays an important role in host defense against viral, bacterial, fungal, and parasitic pathogens, in particular against intracellular bacterial infections, such as Mycobacterium tuberculosis and Listeria monocytogenes.³

High systemic TNF-α levels can lead to septic shock.³ TNF-α has been implicated in the development of allergic diseases, particularly asthma,⁶ and atopic dermatitis.⁷ Serum TNF-α results can be significantly increased in patients with systemic mastocytosis.⁸ The correlation coefficients between highly elevated histamine and cytokine concentrations during the acute phase were >95%, indicating the same cellular origin, possibly activated mast cells.⁸ Elevated TNF-α levels have been associated with worse survival in patients with severe COVID-19 infection.^9-11 Elevated TNF-α levels have been observed in hospitalized patients with acute lung injury.¹²