Vol.3 No.1 (February 2014)
The p38 Mitogen-Activated Protein Kinase Pathway in Rheumatoid Arthritis
Rheumatoid arthritis processes are based on a sustained regulated communication network among different cells types. This network comprises extracellular mediators such as cytokines, chemokines and matrix degrading proteases, which orchestrate the participation of cells in the chronic inflammatory process. Intracellular transcription factor pathways are corresponding with this outside communication world, which transfer information about inflammatory stimuli to the cell nucleus. This review examines the function of one key signal transduction pathway of inflammation—the p38 mitogen-activated protein kinases (p38 MAPK). The p38 MAPK signalling pathway is considered crucial for the induction and maintenance of chronic inflammation, and thus its components emerge as interesting molecular targets of small molecule inhibitors for controlling inflammation. This review not only summarizes the current knowledge of activation, regulation and function of the p38 MAPK pathway but also examines the role of this pathway in rheumatoid arthritis.
陈缙筠 , 吴 虹 , 李 辉 , 代苗苗 , 胡顺莉 , 陈 建 (2014) p38 MAPK通路的活性调控及其在类风湿性关节炎中的作用。 药物资讯， 3， 8-12. doi: 10.12677/PI.2014.31003
 Cohen, D.M. (1997) Mitogen-activated protein kinase cascades and the signaling of hyperosmotic stress to immediate early genes. Comparative Biochemistry and Physiology, 117, 291-299.
 Johnson, G.L. and Lapadat, R. (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science, 298, 1911-1912.
 Sweeney, S.E. and Firestein, G.S. (2004) Signal transduction in rheumatoid arthritis. Current Opinion in Rheumatology, 16, 231237.
 de Launay, D., van de Sande, M.G.H., de Hair, M.J.H., et al. (2012) Selective involvement of ERK and JNK mitogenactivated protein kinases in early rheumatoid arthritis. Annals of the Rheumatic Disease, 71, 415-423.
 Lee, J.C., Laydon, J.T., McDonnell, P.C., et al. (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature, 372, 739-746.
 Gortz, B., Hayer, S., Tuerck, B., et al. (2005) Tumour necrosis factor activates the mitogen-activated protein kinases p38alpha and ERK in the synovial membrane in vivo. Arthritis Research and Therapy, 7, R1140-R1147.
 Caunt, C.J. and Keyse, S.M. (2013) Dual-specificity MAP kinase phosphatases (MKPs): Shaping the outcome of MAP kinase signaling. Federation of European Biochemical Societies Journal, 280, 489-504.
 Xu, Q., Konta, T., Nakayama, K., et al. (2004) Cellular defense against H2O2-induced apoptosis via MAP kinase-MKP-1 pathway. Free Radical Biology and Medicine, 36, 985-993.
 Toh, M.L., Yang, Y., Leech, M., et al. (2004) Expression of mitogen-activated protein kinase phosphatase 1, a negative regulator of the mitogen-activated protein kinases, in rheumatoid arthritis: Up-regulation by interleukin-1beta and glucocorticoids. Arthritis & Rheumatology, 50, 3118-3128.
 Marinissen, M.J., Chiariello, M. and Gutkind, J.S. (2001) Regulation of gene expression by the small GTPase Rho through the ERK6 (p38 gamma) MAP kinase pathway. Genes and Development, 15, 535-553.
 Reedquist, K.A. and Tak, P.P. (2012) Signal transduction pathways in chronic inflammatory autoimmune disease: Small GTPases. The Open Rheumatology Journal, 6, 259-272.
 Yamamoto, A., Fukuda, A., Seto, H., et al. (2003) Suppression of arthritic bone destruction by adenovi-rus-mediated dominantnegative Ras gene transfer to synoviocytes and osteoclasts. Arthritis & Rheumatology, 48, 2682-2692.
 Manzoor, Z. and Koh, Y.S. (2012) Mitogen-activated Protein Kinases in Inflammation. Journal of Bacteriology Virology, 42, 189-195.
 Hammaker, D.R., Boyle, D.L., Chabaud-Riou, M., et al. (2004) Regulation of c-Jun N-terminal kinase by MEKK-2 and mitogen-activated protein kinase kinase kinases in rheumatoid arthritis. Journal of Immunology, 172, 1612-1618.
 Ichijo, H., Nishida, E., Irie, K., et al. (1997) Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/ JNK and p38 signaling pathways. Science, 275, 90-94.
 Takekawa, M., Posas, F. and Saito, H. (1997) A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways. EMBO Journal, 16, 4973-4982.
 Fan, G., Merritt, S.E., Kortenjann, M., et al. (1996) Dual leucine zipper-bearing kinase (DLK) activates p46SAPK and p38mapk but not ERK2. Journal of Biological Chemistry, 271, 2478824793.
 Lu, H.T., Yang, D.D., Wysk, M., et al. (1999) Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO Journal, 18, 1845-1857.
 Inoue, T., Boyle, D.L., Corr, M., et al. (2006) Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis. Proceedings of the National Academy of Sciences of the United States of America, 103, 54845489.
 Chabaud-Riou, M. and Firestein, G.S. (2004) Expression and activation of mitogen-activated protein kinase kinases-3 and -6 in rheumatoid arthritis. The American Journal of Pathology, 164, 177-184.
 Hayer, S., Steiner, G., Gortz, B., et al. (2005) CD44 is a determinant of inflammatory bone loss. Journal of Experimental Medicine, 201, 903-914.
 Gutierrez-Sanmartin, D., Varela-Ledo, E., Aguilera, A., et al. (2008) Implication of p38 mitogen-activated protein kinase isoforms (alpha, beta, gamma and delta) in CD4+ T-cell infection with human immunodeficiency virus type I. Journal of General Virology, 89, 1661-1671.
 Wang, H.X., Xu, Q., et al. (2008) Involvement of the p38 Mitogen-activated Protein Kinase α, β and γ Isoforms in Myogenic Differentiation. Molecular Biology of the Cell, 19, 1519-1528.
 Jiang, Y., Chen, C., Li, Z., et al. (1996) Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). Journal of Biological Chemistry, 271, 17920-17926.
 Cuenda, A., Cohen, P., Buee-Scherrer, V., et al. (1997) Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6), comparison of the specificities of SAPK3 and SAPK2 (RK/p38). EMBO Journal, 16, 295-305.
 Kwong, J., Chen, M., Lv, D., et al. (2013) Induction of p38δ expression plays an essential role in oncogenic ras-induced senescence. Molecular and Cellular Biology, 33, 3780-3794.
 Enslen, H., Raingeaud, J. and Davis, R.J. (1998) Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. Journal of Biological Chemistry, 273, 1741-1748.
 Zarubin, T. and Han, J.H. (2005) Activation and signaling of the p38 MAP kinase pathway. Cell Research, 15, 11-18.
 Korb, A., Tohidast-Akrad, M., Cetin, E., et al. (2006) Differential tissue expression and activation of p38 MAPK alpha, beta, gamma, and delta isoforms in rheumatoid arthritis. Arthritis & Rheumatology, 54, 2745-2756.
 Zwerina, J., Hayer, S., Redlich, K., et al. (2006) Activation of p38 MAPK is a key step in tumor necrosis factor-mediated inflammatory bone destruction. Arthritis & Rheumatology, 54, 463472.
 Miyazawa, K., Mori, A., Miyata, H., et al. (1998) Regulation of interleukin-1beta-induced interleukin-6 gene expression in human fibroblast-like synoviocytes by p38 mitogen-activated protein kinase. Journal of Biological Chemistry, 273, 24832-24838.
 Kotlyarov, A., Neininger, A., Schubert, C., et al. (1999) MAPKAP kinase2 is essential for LPS-induced TNF-alpha biosynthesis. Nature Cell Biology, 1, 94-97.
 O’Dell, J.R. (2004) Therapeutic strategies for rheumatoid arthritis. The New England Journal of Medicine, 350, 2591-602.
 Medicherla, S., Ma, J.Y., Mangadu, R., et al. (2006) A selective p38 alpha mitogen activated protein kinase inhibitor reverses cartilage and bone destruction in mice with collagen induced arthritis. Journal of Pharmacology and Experi-mental Therapeutics, 318, 132-141.
 Revesz, L., Blum, E., Di Padova, F.E., et al. (2004) Novel p38 inhibitors with potent oral efficacy in several models of rheumatoid arthritis. Bioorganic & Medicinal Chemistry Letters, 14, 3595-3599.
 Eom, H.J. and Choi, J. (2010) p38 MAPK activation, DNA damage, cell cycle arrest and apoptosis as mechanisms of toxicity of silver nanoparticles in Jurkat T cells. Environmental Science & Technology, 44, 8337-8342.
 Blom, A.B., van Lent, P.L., Libregts, S., et al. (2007) Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: Involvement of matrix metalloproteinase 3. Arthritis & Rheumatology, 56, 147-157.
 Liacini, A., Sylvester, J., Li, W.Q., et al. (2003) Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases, AP-1, and NFkappaB transcription factors in articular chondrocytes. Experimental Cell Research, 288, 208-217.
 Kim, H.R., Park, M.K., Cho, M.L., et al. (2010) Induction of macrophage migration inhibitory factor in ConA-stimulated rheumatoid arthritis synovial fibroblasts through the P38 MAP kinase-dependent signaling pathway. The Korean Journal of Internal Medicine, 25, 317-326.
 Schett, G., Hayer, S., Zwerina, J., et al. (2005) Mechanisms of disease: The link between RANKL and arthritic bone disease. Nature Clinical Practice Rheumatology, 1, 47-54.
 Tao, H., Okamoto, M., Nishikawa, M., et al. (2011) P38 mitogen-activated protein kinase inhibitor, FR167653, inhibits parathyroid hormone related protein-induced osteoclastogenesis and bone resorption. PLoS One, 6, 1-8.
 Goebeler, M., Kilian, K., Gillitzer, R., et al. (1999) The MKK6/ p38 stress kinase cascade is critical for tumor necrosis factoralpha-induced expression of monocyte chemoattractant protein-1 in endothelial cells. Blood, 93, 857-865.
 Ono, H., Ichiki, K., Ohtsubo, H., et al. (2006) cAMP-response element-binding protein mediates tumor necrosis factor—induced vascular cell adhesion molecule-1 expression in endothelial cells. Hypertension Research, 29, 39-47.
 Niwa, K., Inanami, O., Ohta, T., et al. (2001) P38 MAPK and Ca2+ contribute to hydrogen peroxide-induced increase of permeability in vascular endothelial cells but ERK does not. Free Radical Research, 35, 519-527.