Tumour Necrosis Factor Alpha (TNF-alpha)

Tumour necrosis factor alpha is a trimeric cytokine made as a membrane-bound 26 kilodalton precursor and cleaved by ADAM17 to a soluble 17 kilodalton form. Both forms signal. TNFR1 is on nearly all nucleated cells and carries a death domain, so it can drive survival and inflammation or apoptosis, depending on the complex assembled beneath it; TNFR2 is restricted largely to immune and endothelial cells. It is among the strongest activators of nuclear factor kappa B and also one of its products.

Five inhibitors are approved: infliximab, adalimumab, golimumab and certolizumab pegol are antibody-based, etanercept a soluble receptor fusion protein. They transformed rheumatoid arthritis, psoriasis, ankylosing spondylitis and inflammatory bowel disease. The class carries a boxed warning for serious infection, particularly reactivation of latent tuberculosis, because the cytokine maintains granulomas, and a warning about lymphoma; screening before initiation is routine.

The class also shows that blocking a cytokine is not one mechanism. Etanercept works in rheumatoid arthritis but failed in Crohn's disease, where the antibodies succeed, a difference usually attributed to how the formats engage membrane-bound cytokine. Trials in chronic heart failure showed no benefit and signals of harm, ending an approach that had looked justified.

The measurement error is treating the circulating concentration as an inflammation readout. Plasma levels in healthy people sit at or below the detection limit of most immunoassays, the half-life is minutes, and it acts largely within tissue, so serum values track disease activity poorly. A report that a compound lowers it in mice given lipopolysaccharide describes one acute response suppressed, a long way from what an approved inhibitor does in a joint.