Tumor Necrosis Factor-Like Weak Inducer of Apoptosis

The Tumor Necrosis Factor-Like Weak Inducer of Apoptosis is a member of the TNF superfamily (see TNF gene below), which was originally shown to induce apoptosis of malignant cells. It is synthesized in the form of a transmembrane protein (mTWEAK) and proteolytically processed into a soluble cytokine (sTWEAK). Monocytes/macrophages are the main source of sTWEAK in inflammatory tissues. The TWEAK/Fn14 signaling pathway is involved in chronic human inflammatory diseases such as neurodegenerative, autoimmune or malignant diseases.

In contrast to TNF-α, TWEAK inhibits the innate immune response and attenuates the transition to adaptive Th1 immunity (Maecker H et al. 2005; Nakayama M et al.2000; Desplat-Jégo S et al. 2009). In addition, TWEAK inhibits TNF receptor 1 signaling, which promotes inflammation (Wicovsky A et al. 2009).

TWEAK signaling mainly requires binding to Fn14, a member of the TNF receptor superfamily (TNFRSF). TNFRSFs are type I transmembrane proteins characterized by the presence of multiple extracellular cysteine-rich domains responsible for ligand binding. The TNFRSF protein Fn14 is the tumor necrosis factor-like weak apoptosis inducer (TWEAK) receptor. Fn14 was primarily described in fibroblasts as fibroblast growth factor-inducible-14. Although Fn14 is hardly expressed in healthy endothelial cells, neurons, astrocytes, microglia and progenitor cells, it is highly inducible in these cells. The interaction of TWEAK with its (Fn14) receptor triggers several molecular events and biological responses depending on the cell type and microenvironment (Bhattacharjee M et al. 2012)

These downstream signaling pathways include a large number of proteins and inducible genes. Accordingly, the interaction of TWEAK with its Fn14 receptor primarily activates nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) via interaction with intracellular TNF receptor-associated factors. mTWEAK appears to activate the canonical NF-κB signaling pathway more efficiently, while both membrane-bound and soluble TWEAK can induce the non-canonical NF-κB signaling pathway (Roos C et al. 2010). In the CNS, TWEAK acts on endothelial cells, astrocytes and neurons. Interestingly, the TWEAK/Fn14 signaling pathway can stimulate reactivity in mouse and human astrocytes. This associated mitogenic potency is mediated by the TWEAK-induced MAPK signaling pathway (Rousselet E et al. (2012).

In vitiligo patients, TWEAK serum levels were significantly higher than in control subjects (644.76 ± 688.93 vs. 282.75 ± 125.67, respectively). Serum levels were significantly higher in segmental vitiligo than in non-segmental vitiligo. Receiver operating characteristic (ROC) analysis showed that TWEAK had 80% sensitivity and 56.67% specificity in diagnosing vitiligo and 100% sensitivity and 80.09% specificity in distinguishing segmental from non-segmental vitiligo (El-Taweel AEI et al. 2021).

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