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World J Pharmacol. Dec 9, 2015; 4(4): 265-273
Published online Dec 9, 2015. doi: 10.5497/wjp.v4.i4.265
Role of mitogen- and stress-activated kinases in inflammatory arthritis
Sylvain G Bourgoin, Weili Hui
Sylvain G Bourgoin, Weili Hui, Division of Infectious Disease and Immunity, CHU de Québec Research Center and Department of Microbiology-Infectious Disease and Immunology, Faculty of Medicine, Laval University, Québec G1V 4G2, Canada
Author contributions: Hui W made the review of the literature, wrote the manuscript, and prepared the figure; Bourgoin SG supervised the writing and made important revisions related to the content of the manuscript.
Supported by A research grant from the Arthritis Society of Canada, No. RG10/011 (to Bourgoin SG).
Conflict-of-interest statement: Authors declare no conflict of interest for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Sylvain G Bourgoin, PhD, Division of Infectious Disease and Immunity, CHU de Québec Research Center and Department of Microbiology-Infectious Disease and Immunology, Faculty of Medicine, Laval University, 2705 Boul Laurier, Québec G1V 4G2, Canada. sylvain.bourgoin@crchudequebec.ulaval.ca
Telephone: +1-418-5254444-46136 Fax: +1-418-6542765
Received: May 29, 2015
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
Processing time: 193 Days and 12 Hours
Abstract

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.

Keywords: Lysophosphatidic acid; Mitogen activated protein kinase; Chemokines; Cytokines; Mitogen- and stress-activated kinases; Inflammation; cAMP response element-binding protein; Arthritis

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.