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In rheumatoid and other kinds of inflammatory arthritis, a number of different cell types undergo activation to produce inflammation and joint destruction. These include T and B lymphocytes, macrophages, neutrophils and synovial fibroblasts. In recent years much arthritis research has focused on the interactions between these cells via cytokines. Far less attention has been devoted to the actual intracellular processes through which these cells undergo activation. These intracellular processes--known collectively as signal transduction--are the focus of our laboratory, particularly as they relate to neutrophils (inflammation) and synovial fibroblasts (synovial proliferation and bony erosion). |
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The mitogen-activated protein kinases (MAPKs) are a family of enzymes which, in response to extracellular signals, target and phosphorylate specific serines and threonines in effector proteins, leading to cellular responses. Three classes of MAPKs have been identified: Jnk and p38, which classically respond to stress signals, and Erk, which classically plays a role in cell development and division in response to agents such as epidermal growth factor (EGF). Our studies of signaling in arthritis-related cells has focused intensively, though not exclusively, on the role(s) of MAPKs. We have shown that Erk is rapidly activated in neutrophils in response to chemoattractants such as formylmethionyl-leucyl-phenylalanine (FMLP) and is necessary for stimulated neutrophil adhesion, an important early step in acute inflammation. We have also shown that Erk in synovial fibroblasts is stimulated by interleukin-1 (Il-1) and tumor necrosis factor--two cytokines of paramount importance in rheumatoid arthritis--and that inhibition of Erk in these cells blocks the release of an important tissue-degrading metalloproteinase enzyme (MMP-1). Strikingly, Erk activation in both neutrophils and synovial fibroblasts is inhibited by salicylates, indicating a potentially important and previously unappreciated mechanism for the action of these drugs. We believe that studies such as ours are essential for a deeper understanding of inflammatory arthritis, and that the identification of the intracellular pathways involved in arthritis cell activation will be critical for the development of more effective antiarthritis agents. |
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