@article {Santos1038, author = {Leilani L Santos and Derek Lacey and Yuanhang Yang and Michelle Leech and Eric F Morand}, title = {Activation of synovial cell p38 MAP kinase by macrophage migration inhibitory factor.}, volume = {31}, number = {6}, pages = {1038--1043}, year = {2004}, publisher = {The Journal of Rheumatology}, abstract = {OBJECTIVE: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine important in animal models of rheumatoid arthritis (RA). We investigated the utilization by MIF of mitogen activated protein (MAP) kinase signalling pathways in the stimulation of fibroblast-like synoviocytes (FLS), cyclooxygenase-2 (COX-2), prostaglandin E(2) (PGE(2)), and interleukin 6 (IL-6) and IL-8 expression. METHODS: Cultured human RA FLS were treated with recombinant MIF. Activation of MAPK was measured by Western blotting and blocked using specific inhibitors. The expression of COX-2, PGE(2), IL-6, and IL-8 were measured using flow cytometry, ELISA, and real-time polymerase chain reaction. RESULTS: MIF induced the phosphorylation of FLS p38 and extracellular-signal regulated kinase (ERK) MAP kinase. MIF significantly induced COX-2 and IL-6 protein and mRNA expression as well as PGE(2) and IL-8 production. Antagonism of p38 MAP kinase inhibited MIF induction of COX-2, PGE(2), and IL-6. In contrast, antagonism of ERK had no effect on COX-2, PGE(2), or IL-6. Neither antagonist inhibited MIF-induced IL-8. CONCLUSION: MIF activates RA FLS COX-2 and IL-6 expression via p38 MAP kinase activation and induces IL-8 via p38 and ERK MAP kinase-independent pathways.}, issn = {0315-162X}, URL = {https://www.jrheum.org/content/31/6/1038}, eprint = {https://www.jrheum.org/content/31/6/1038.full.pdf}, journal = {The Journal of Rheumatology} }