Immunoregulatory role of TNFα in inflammatory kidney diseases

Tumor necrosis factor alpha (TNF alpha), a pleiotropic cytokine, plays important inflammatory roles in renal diseases such as lupus nephritis, anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis and renal allograft rejection. However, TNF alpha also plays critical immunoregulatory roles that are required to maintain immune homeostasis. These complex biological functions of TNF alpha are orchestrated by its two receptors, TNFR1 and TNFR2. For example, TNFR2 promotes leukocyte infiltration and tissue injury in an animal model of immune complex-mediated glomerulonephritis. On the other hand, TNFR1 plays an immunoregulatory function in a murine lupus model with a deficiency in this receptor that leads to more severe autoimmune symptoms. In humans, proinflammatory and immunoregulatory roles for TNF alpha are strikingly illustrated in patients on anti-TNF alpha medications: These treatments are greatly beneficial in certain inflammatory diseases such as rheumatoid arthritis but, on the other hand, are also associated with the induction of autoimmune lupus-like syndromes and enhanced autoimmunity in multiple sclerosis patients. The indication for anti-TNF alpha treatments in renal inflammatory diseases is still under discussion. Ongoing clinical trials may help to clarify the potential benefit of such treatments in lupus nephritis and ANCA-associated glomerulonephritis. Overall, the complex biology of TNF alpha is not fully understood. A greater understanding of the function of its receptors may provide a framework to understand its contrasting proinflammatory and immunoregulatory functions. This may lead the development of new, more specific anti-inflammatory drugs. Kidney International (2009) 76, 262-276; doi:10.1038/ki.2009.142; published online 13 May 2009