Tumor necrosis factor and mitogen-activated protein kinase signaling pathways (TNF/MAPK pathways)

The TNF and MAPK signaling pathways are two major, highly integrated intracellular communication networks that govern critical cellular processes such as inflammation, immunity, cell survival, and apoptosis [1, 3]. Tumor Necrosis Factor (TNF) is a master pro-inflammatory cytokine that initiates signaling by binding to its cognate receptors, TNFR1 and TNFR2, which subsequently recruit adaptor proteins like TRADD and TRAF2 to activate downstream cascades, most notably the Mitogen-Activated Protein Kinase (MAPK) pathways [5, 7]. The MAPK family, comprising ERK, JNK, and p38, acts as a bridge between extracellular stimuli and the transcriptional machinery of the cell, regulating the expression of cytokines and other mediators that drive the inflammatory response [1, 2]. Chronic overactivation of these pathways is strongly linked to the pathogenesis of autoimmune and inflammatory disorders, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease, as well as the progression of various cancers [1, 14, 15]. This entry is considered incorrect as a single therapeutic target because it encompasses two distinct signaling pathways rather than a specific molecular entity. Therapeutic strategies targeting these pathways involve biologic agents like adalimumab and infliximab that neutralize TNF or small-molecule inhibitors like trametinib that target specific kinases within the MAPK cascade [13, 14, 16].

Other names

TNF-MAPK signaling networkTNF-alpha and MAP kinase pathwaysTNF-MAPK axis

Neutralization of soluble and membrane-bound TNF-alpha to prevent receptor binding; Inhibition of MEK1/2 or p38 kinases to block downstream signaling cascades.