Published online Dec 9, 2015. doi: 10.5497/wjp.v4.i4.265
Peer-review started: June 1, 2015
First decision: August 4, 2015
Revised: September 10, 2015
Accepted: October 16, 2015
Article in press: October 19, 2015
Published online: December 9, 2015
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 cAMP 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.
Core tip: Extracellular signal-regulated kinases 1/2 and p38 mitogen activated protein kinase cascades are activated in response to stimulation with inflammatory stimuli, including lysophosphatidic acid, and are able to activate mitogen- and stress-activated kinase (MSK) 1 and MSK2 in human synovial fibroblasts. MSKs then phosphorylate the transcription factor cAMP response element-binding protein (CREB), leading to the production of pro-inflammatory and anti-inflammatory cytokines. In addition to CREB, many other downstream effectors of MSK1/2 such as nuclear factor-kappa B, histone H3, the E3 ubiquitin ligase, Tripartite motif containing 7 and high mobility group nucleosome binding domain 1 have been reported and suggested to play important functions in immunity and disease states, including arthritis.