Interleukin-17 family

The interleukin-17 family comprises six structurally related cytokines, IL-17A through IL-17F, that act at epithelial and mucosal surfaces to recruit neutrophils, induce antimicrobial peptides and amplify local inflammation. IL-17A and IL-17F are the central members, secreted as homodimers or as an IL-17A/F heterodimer, and signal through a receptor complex of IL-17RA with IL-17RC. That receptor is unlike most cytokine receptors: it uses neither JAK/STAT nor a kinase of its own, but recruits the adaptor Act1, which engages TRAF6 to activate NF-κB and MAPK pathways — although IL-17 receptor signaling itself does not respond to JAK inhibitors, IL-17-driven disease can respond to them and has its own class of drugs. The family is functionally heterogeneous, IL-17E (IL-25) driving type 2 rather than neutrophilic responses.

IL-17 is the effector arm of the Th17 program, and its production is induced and sustained upstream by interleukin-23, which is a driver of the response rather than a product of it. Downstream, IL-17 acts largely by amplification: it induces NF-κB-dependent expression of Tnf-α, Interleukin-6 (IL-6), IL-1β, chemokines and growth factors, and synergizes with Tnf-α so that the two together do far more than either alone. Its physiological role is defense against extracellular bacteria and fungi at barrier surfaces, which is why patients with genetic defects in IL-17 signaling — and, more mildly, those given IL-17 blockers — develop chronic mucocutaneous candidiasis.

Blocking the axis is highly effective in plaque psoriasis and psoriatic arthritis, where secukinumab and ixekizumab neutralize IL-17A, brodalumab blocks the receptor, and bimekizumab neutralizes both IL-17A and IL-17F. The same blockade fails in Crohn's disease and can worsen it, consistent with IL-17's role in maintaining intestinal barrier integrity — a clear demonstration that a cytokine's contribution is tissue-specific rather than uniformly pathogenic. Research continues into IL-17 signaling in osteoarthritis, periodontitis, experimental autoimmune encephalomyelitis, neuroinflammation and antiviral responses.