Role of mitogen- and stress-activated kinases in inflammatory arthritis

Lysophosphatidic acid(LPA) is a pleiotropic lipid mediator that promotes motility, survival, and the synthesis of chemokines/cytokines in human fibroblast-like synoviocytes(FLS) from patients with rheumatoid arthritis. LPA activates several proteins within the mitogen activated protein(MAP) kinase signaling network, including extracellular signal-regulated kinases(ERK) 1/2 and p38 MAP kinase(MAPK). Upon docking to mitogen- and stress-activated kinases(MSKs), ERK1/2 and p38 MAPK phosphorylate serine and threonine residues within its C-terminal domain and cause autophosphorylation of MSKs. Activated MSKs can then directly phosphorylate c AMP response element-binding protein(CREB) at Ser133 in FLS. Phosphorylation of CREB by MSKs is essential for the production of pro-inflammatory and anti-inflammatory cytokines. However, other downstream effectors of MSK1/2 such as nuclear factor-kappa B, histone H3, and high mobility group nucleosome binding domain 1 may also regulate gene expression in immune cells involved in disease pathogenesis. MSKs are master regulators of cell function that integrate signals induced by growth factors, pro-inflammatory cytokines, and cellular stresses, as well as those induced by LPA.