Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling via p38 mitogen-activated protein kinase (MAPK) axis (NF-κB/p38 MAPK axis)

The Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling via p38 mitogen-activated protein kinase (MAPK) axis represents a major regulatory circuit in macrophages that integrates extracellular stress and inflammatory signals to drive the expression of pro-inflammatory genes (Saha et al., 2007). Activation of p38 MAPK, often via the MKK3/6 pathway, leads to the enhancement of NF-κB transcriptional activity either by direct phosphorylation of the p65 subunit or by modulating the IKK complex (Cuenda & Rousseau, 2007). This synergy is essential for the rapid production of cytokines like Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-1 beta (IL-1β) during the innate immune response (O'Dea & Hoffmann, 2010). However, persistent activation of this axis is linked to chronic inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease, as well as the promotion of pro-tumorigenic environments in cancer (Schieven, 2005). Pharmacological targeting of this axis primarily involves p38 MAPK inhibitors, such as Losmapimod, which aim to dampen the inflammatory output of macrophages (Goldstein et al., 2010). Despite their potential, many such inhibitors have faced clinical hurdles due to off-target toxicities and the activation of compensatory signaling pathways.

Other names

NF-kappaB signaling via p38 MAPK axisp38-NF-kappaB pathwayp38 MAPK-mediated NF-kappaB activationp38 MAPK-NF-kappaB axis

Inhibition of p38 MAPK prevents the phosphorylation of downstream kinases or transcription factor subunits (like p65), thereby reducing NF-κB-mediated transcription of pro-inflammatory genes.