The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting

TWEAK, a member of the tumour necrosis factor superfamily, is a multifunctional cytokine that acts on cells by binding to a small cell-surface receptor named Fn14. Here, Winkles summarizes the biology of the TWEAK–Fn14 axis and describes the recent evidence supporting the notion that this axis could be a therapeutic target for the treatment of cancer, chronic autoimmune diseases and acute ischaemic stroke. TWEAK is a multifunctional cytokine that controls many cellular activities including proliferation, migration, differentiation, apoptosis, angiogenesis and inflammation. TWEAK acts by binding to Fn14, a highly inducible cell-surface receptor that is linked to several intracellular signalling pathways, including the nuclear factor-κB (NF-κB) pathway. The TWEAK–Fn14 axis normally regulates various physiological processes, in particular it seems to play an important, beneficial role in tissue repair following acute injury. Furthermore, recent studies have indicated that TWEAK–Fn14 axis signalling may contribute to cancer, chronic autoimmune diseases and acute ischaemic stroke. This Review provides an overview of TWEAK–Fn14 axis biology and summarizes the available data supporting the proposal that both TWEAK and Fn14 should be considered as potential targets for the development of novel therapeutics.