TNF-α, TNF Receptors and Their Complex Implications in Therapy

Tumor necrosis factor alpha (TNF-α), also called cachectin or cachexin, is a naturally occurring cytokine produced by activated macrophages and monocytes, and to a smaller scale by T-lymphocytes, B-lymphocytes, fibroblasts and astrocytes. It has both inflammatory and immunomodulatory roles effectuated through its action on tumor necrosis factor receptor-1 (TNFR1) and tumor necrosis factor receptor-2 (TNFR2). TNF-α overexpression (especially of TNFR1 mediated actions) or under expression (especially of TNFR2 mediated actions) may contribute to several diseases including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and juvenile inflammatory arthritis. Several anti-TNF therapies are proven to be beneficial in these diseases, including etanercept, infliximab, adalimumab, certolizumab and golimumab.

Biological responses of TNF-α include inflammation, apoptosis, immunomodulation, tissue repair, antiviral and antitumor activity and mediation of endotoxin-induced septic shock, recruitment of inflammatory cells including neutrophils, monocytes and lymphocytes to sites of infection; and cell activation through action on different receptors (TNFR1 and TNFR2).

Low grade chronic inflammation occurs in several other diseases including atherosclerosis, hypertension, chronic kidney disease, Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. Researchers have explored whether anti-TNF therapies can be helpful in these diseases too. Both positive and negative effects of anti-TNF therapies have been observed in these diseases. These observations suggest that TNF-α and TNF receptors system have an incredibly complex pathophysiologic role, and hence blockade of this pathway results in complex effects on different organ systems. In this review we have explored the myriad effects on various organ systems due to TNF blockade, including COVID-19.