The p38 mitogen-activated protein kinasa (MAPK) pathway mediates induction of the tissue factor gene in monocytes stimulated with human monoclonal anti β2Glycoprotein I antibodies

• Project/Area Number: 15390310
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: HOKKAIDO UNIVERSITY
• Principal Investigator: KOIKE Takao Hokkaido Univ., Grad.School of Med., Prof., 大学院・医学研究科, 教授 (80146795)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥12,200,000 (Direct Cost: ¥12,200,000); Fiscal Year 2004: ¥5,500,000 (Direct Cost: ¥5,500,000); Fiscal Year 2003: ¥6,700,000 (Direct Cost: ¥6,700,000)
• Keywords: antiphospholipid syndrome (APS) / p38 MAPK / Anticardiolipin antibodies / β_2Glycoprotein I / phospholipid / p38MAPK / 血栓症 / プロトロンビン

Research Abstract

The antiphospholipid syndrome (APS) is characterized by thrombosis and the presence of antiphospholipid antibodies (aPL). Tissue factor (TF), the major initiator of the coagulation system, is induced on monocytes by aPL in vitro, explaining, in part, the pathophysiology in this syndrome. However, little is known regarding the nature of the aPL-induced signal transduction pathways leading to TF expression. In this study, we investigated aPL inducible genes in peripheral blood mononuclear cell (PBMC) using cDNA array system and real time polymerase chain reaction (PCR). Our results indicated that the mitogen-activated protein kinase (MAPK) pathway was related to TF expression when PBMCs were treated, in the presence of β_2Glycoprotein I (β_2GPI), with human monoclonal anti-β_2GPI antibodies (β_2GPI dependent anticardiolipin antibodies ; aCL/β_2GPI). Western blotting studies using monocyte cell line (RAW264.7) demonstrated that p38 MAPK protein was phosphorylated with NF-κB (nuclear factor κ B) activation by monoclonal aCL/β_2GPI treatment, and that SB203580, a specific p38 MAPK inihibitor, decreased the aCL/β_2GPI-induced TF mRNA expression. The p38 MAPK phosphorylation, NF-κB translocation and TF mRNA expression triggered by aCL/β_2GPI were abolished in the absence of β_2GPI. These results demonstrated that the p38 MAPK signaling pathway plays an important role in aPL-induced TF expression on monocytes and suggest that the p38 MAPK may be a possible therapeutic target to modify a prothrombotic state in patients with APS.

Research Products

• [Journal Article] Significance of valine/leucine^<247> polymorphism of β2-glycoprotein I in antiphospholipid syndrome : increased reactivity of anti-β2-glycoprotein I autoantibodies to the valine^<247> β2-glycoprotein I variant (2005)
  • Author(s): Yasuda S, Atsumi T, Matsuura E, Kaihara K, Yamamoto D, Ichikawa K, Koike T.
  • Journal Title: Arthritis Rheum 51:2 Pages: 212-218
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Significance of valine/leucine^<247> polymorphism of β2-glycoprotein I in antiphospholipid syndrome : increased reactivity of anti-β_2-glycoprotein I autoantibodies to the valine^<247> β_2-glycoprotein I variant (2005)
  • Author(s): Yasuda S, Atsumi T, Matsuura E, Kaihara K, Yamamoto D, Ichikawa K, Koike T.
  • Journal Title: Arthritis Rheum 51:2 Pages: 212-218
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Gain-of-function polymorphism in mouse and human Ltk : implications for the pathogenesis of lupus erythematosus. (2004)
  • Author(s): Li, N., Nakamura, K., Jiang, Y., Tsurui, H., Matsuoka, S., Abe, M., Ohtsuji, M., Nishimura, H., Kato, K., Kawai, T., Atsumi, T., Koike, T., Shirai, T., Ueno, H., Hirose, S
  • Journal Title: Hum Mol Genet 13:2 Pages: 171-179
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Antiprothombin antibodies and the diagnosis of antiphospholipid syndrome. (2004)
  • Author(s): Amengual, O., Atsumi.T., Koike, T
  • Journal Title: Clin Immunol 112 Pages: 144-149
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Novel negative regulator of expression in Fas Ligand (CD178) Cytoplasmic tail : Evidence for Translational Regulation and against Pas Ligand Retention in secretory lysosomes. (2004)
  • Author(s): Xiao, S., Deshmukh, S.U., Jodo, S., Koike, T., Sharma, R., Furusaki, A., Sung, J.S., Ju, Shyr-Tu.
  • Journal Title: J Immunol 173 Pages: 5095-5102
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Nicked beta2-glycoprotein I : A marker of cerebral infarct and a novel rote in the negative feedback pathway of extrinsic fibrinolysis. (2004)
  • Author(s): Yasuda S., Atsumi T., Ieko, M., Matsuura, E., Kobayashi, K., Inagaki, J., Kato, H., Tanaka, H., Yamakado, M., Akino, M., Saitou, H., Amasaki, Y., Jodo, S., Amengual O., Koike, T.
  • Journal Title: Blood 103:10 Pages: 3766-3772
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The p38 mitogen-activated protein kinasa (MAPK) pathway mediates induction of the tissue factor gene in monocytes stimulated with human monoclonal anti-β2Glycoprotein I antibodies. (2004)
  • Author(s): Bohgaki, M., Atsumi, T., Yamashita, Y., Yasuda, S., Sakai, Y., Furusaki, A., Bohgaki, T., Amengual, O., Amasaki, Y., Koike, T.
  • Journal Title: J Clin Immunol 23:5 Pages: 375-375
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Oculocutaneous albinism type 4 is one of the most common types of albinism in Japan. (2004)
  • Author(s): Inagaki K, et al.
  • Journal Title: Am J Hum Genet 74 Pages: 466-471
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The G2028R glycine substitution mutation in COL7A1 leads to marked inter-familiar clinical heterogeneity in dominant dystrophic epidermolysis bullosa. (2004)
  • Author(s): Nakamura H, et al.
  • Journal Title: J Dermatol Sci 34 Pages: 195-200
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] An elderly patient with mycosis fungoides successfully treated with chronic low-dose oral etoposide therapy. (2004)
  • Author(s): Onozuka T, et al.
  • Journal Title: Clin Exp Dermatol 29 Pages: 91-92
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Characterization of Kdap, a protein secreted by keratinocytes. (2004)
  • Author(s): Tsuchida S, et al.
  • Journal Title: J Invest Dermatol 122 Pages: 1225-1234
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Ultraviolet A-induced production of matrix metalloproteinase-1 is mediated by macrophage migration inhibitory factor (MIF) in human dermal fibroblasts. (2004)
  • Author(s): Watanabe H, et al.
  • Journal Title: J Biol Chem 279 Pages: 1676-1683
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Novel negative regulator of expression in Fas Ligand (CD178) Cytoplasmic tail : Evidence for Translational Regulation and against Fas Ligand Retention in secretory lysosomes. (2004)
  • Author(s): Xiao, S., Deshmukh, S.U., Jodo, S., Koike, T., Sharma, R., Furusaki, A., Sung, J.S., Ju, Shyr-Tu.
  • Journal Title: J Immunol 173 Pages: 5095-5102
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nicked beta2-glycoprotein I : A marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis. (2004)
  • Author(s): Yasuda, Atsumi T, Ieko, M., Matsuura, E., Kobayashi, K., Inagaki, J., Kato, H., Tanaka, H., Yamakado, M., Akino, M., Saitou, H., Amasaki, Y., Jodo, S., Amengual O, Koike, T.
  • Journal Title: Blood 103:10 Pages: 3766-3772
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The p38 mitogen-activated protein kinasa (MAPK) pathway mediates induction of the tissue factor gene in monocytes stimulated with human monoclonal anti β2Glycoprotein I antibodies. (2004)
  • Author(s): Bohgaki, M., Atsumi, T., Yamashita, Y., Yasuda, S., Sakai, Y., Furusaki, A., Bohgaki, T., Amengual, O., Amasaki, Y., Koike, T.
  • Journal Title: J Crin Immunol 23:5 Pages: 375-375
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antiprothombin antibodies and the diagnosis of antiphospholipid syndrome. (2004)
  • Author(s): Amengual, O., Atsumi, T., Koike, T
  • Journal Title: Clin Immunol 112 Pages: 144-149
• [Journal Article] Novel negative regulator of expression in Fas Ligand(CD178)Cytoplasmic tail : Evidence for Translational Regulation and against Fas Ligand Retention in secretory lysosomes. (2004)
  • Author(s): Xiao, S., Deshmukh, S.U., Jodo, S., Koike, T., Sharma, R., Furusaki, A., Sung, J.S., Ju, Shyr-Tu.
  • Journal Title: J Immunol 173 Pages: 5095-5102
• [Journal Article] The p38 mitogen-activated protein kinasa(MAPK)pathway mediates induction of the tissue factor gene in monocytes stimulated with human monoclonal anti-β2Glycoprotein I antibodies. (2004)
  • Author(s): Bohgaki, M., Atsumi, T., Yamashita., Y., Yasuda, S., Sakai, Y., Furusaki, A., Bohgaki, T., Amengual, O., Amasaki, Y., Koike, T.
  • Journal Title: J Clin Immunol 23:5 Pages: 375-375
• [Journal Article] Epidermolysis bullosa simplex in Oriental ; genetic studies in 19 patients
  • Author(s): Yasukawa K, et al.
  • Journal Title: Br J Dermatol (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Systemic Lupus Erythematosus 4rd edition.(Lahita RG ed.) (2004)
  • Author(s): Atsumi, T., Matsuura, E., Koike, T.
  • Total Pages: 1343
  • Publisher: Harcourt Brace & Company.
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Immunology of anti-phospholipid antibodies and cofactors. (Systemic Lupus Erythematosus 4rd edition. Lanita RG ed.) (2004)
  • Author(s): Atsumi, T., Matsuura, E., Koike, T.
  • Total Pages: 1343
  • Publisher: Harcourt Brace & Campany
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Systemic Lupus Erythematosus 4rd edition.(Immunology of anti-phospholipid antibodies and cofactors.)(Lahita RG ed.) (2004)
  • Author(s): Atsumi, T., Matsuura, E., Koike, T.
  • Total Pages: 1343
  • Publisher: Harcourt Brace & Campany.
• [Publications] Yasuda, Atsumi T, Ieko, M., Matsuura, E., Kobayashi, K., Inagaki, J., Kato, H., Tanaka, H., Yamakado, M., Akino, M., Saitou, H., Amasaki, Y., Jodo, S., Amengual O, Koike, T.: "Nicked beta2-glycoprotein I : A marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis"Blood. (in press).
• [Publications] Li, N., Nakamura, K., Jiang, Y., Tsurui, H., Matsuoka, S., Abe, M., Ohtsuji, M., Nishimura, H., Kato K., Kawai, T., Atsumi, T., Koike, T., Shirai, T., Ueno, H., Hirose, S: "Gain-of-function polymorphism in mouse and human Ltk : implications for the pathogenesis of lupus erythematosus"Hum Mol Genet1. 3:2. 171-179 (2004)
• [Publications] Sakai, Y., Atsumi, T., Itoh, T., Koike, T: "Uveitis, pancardotos, haemophagocytosis, and abdominal masses"Lancet. 361 : 9360. 834 (2003)
• [Publications] Amengual O, Atsumi T, Koike T.: "Specificities, properties, and clinical significance of antiprothrombin antibodies"Arthritis Rheum. 48 : 4. 886-895 (2003)
• [Publications] Oku K, Atsumi T, Furukawa S, Horita T, Sakai Y, Jodo S, Amasaki Y, Ichikawa K, Amengual O, Koike T.: "Cerebral imaging by magnetic resonance imaging and single photon emission computed tomography in systemic lupus erythematosus with central nervous system involvement"Rheumatol.. 48 : 4. 886-895 (2003)
• [Publications] Shoenfeld Y, Krause I, Kvapil F, Sulkes J, Lev S, Landenberg P, Font J, Zaech J, Cervera R, Piette J, Boffa M, Khamashta M, Bertolaccini M, Hughes G, Youinou P, Meroni P, Pengo V, Alves J, Tincani A, Szegedi G, Lakos G, Sturfelt G, Jonsen A, Koike T, Sanmarcp M, Ruffatti A, Ulcova-gallova Z, Praprotnic S, Rozman B, Lorber M, Vriezman V.: "Prevalence and Clinical Correlations of Antibodies Against Six β2-Glycoprotein-I-Related Peptides in the Aintiphospholipid Syndrome"J Clin Immunol. 23 : 5. 375 (2003)
• [Publications] Wu R, Shoenfeld Y, Sherer Y, Patnaik M, Matsuura E, Gilburd B, Koike T, Peter JB.: "Anti-idiotypes to oxidized LDL antibodies in intravenous immunoglobulin preparations--possible immunomodulation of atherosclerosis"Autoimmunity. 36 : 2. 91-97 (2003)