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Interleukin 26 (IL-26) is a pro-inflammatory cytokine and a member of the IL-10 family, primarily produced by T helper 17 (Th17) cells and natural killer (NK) cells [3, 4, 16]. It is uniquely characterized by its dual role as a signaling molecule and an antimicrobial peptide (kinocidin) that can directly kill extracellular bacteria through membrane-pore formation [3, 7, 15]. IL-26 signals through a heterodimeric receptor complex consisting of IL-20 receptor 1 (IL-20R1) and IL-10 receptor 2 (IL-10R2), primarily activating the JAK-STAT3 pathway to induce the production of various pro-inflammatory cytokines like IL-8 and TNF-alpha [2, 3, 21]. Beyond its receptor-mediated effects, IL-26 can bind to extracellular DNA and facilitate its entry into cells, triggering intracellular innate immune sensors like Toll-like receptor 9 (TLR9) [3, 6, 15]. Pathologically, elevated IL-26 levels are associated with various chronic inflammatory diseases, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease, as well as several cancers such as triple-negative breast cancer [7, 12, 15, 20]. Consequently, IL-26 has emerged as a promising therapeutic target, with neutralizing monoclonal antibodies and vaccines currently under investigation to mitigate its role in pathological inflammation and tumor progression [2, 8, 10].
Neutralization of the IL-26 ligand to prevent its binding to the IL-20R1/IL-10R2 receptor complex, thereby inhibiting activation of the JAK-STAT signaling pathway and the subsequent induction of pro-inflammatory cytokines [2, 15, 21]. Additionally, targeting IL-26 can disrupt the formation of IL-26/DNA complexes, preventing the delivery of extracellular DNA to intracellular innate immune sensors like TLR9 and STING [3, 15, 18].
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