臺灣博碩士論文加值系統

全身紅斑性狼瘡（SLE）是一種慢性自體免疫疾病，患者臉部有明顯的蝴蝶狀紅斑，身上並伴隨有狼瘡腎炎、關節炎等症狀，最大特徵是血液中有大量抗核抗體等自體抗體的存在。自體抗體與自體抗原結合後會沈積在器官中，造成器官的損害。
之前本研究室已發現抗雙股DNA單株自體抗體（9D7）會與Jurkat細胞中的phosphoglycerate kinase 1（PGK-1）有交叉反應，因此本論文進一步探討9D7抗體與PGK-1的交叉反應點。PGK-1的結構兩端各有一個催化區（catalytic domain, CD），中間為核甘酸反應區（nucleotide binding domain, NBD），最主要的功能是參與催化糖解作用。我們利用大腸桿菌生產出四種剔除變異型PGK-1（PGK△CDII、PGK△CDI、PGK-CDI、PGK-NBD），以西方墨點法分析發現，9D7抗體對PGK-1之反應點主要為靠近5’端的催化區（PGK- CDI）。
此外，之前研究發現9D7抗體處理Jurkat細胞，會抑制Jurkat細胞IL-2 promoter活性及IL-2 mRNA之表現量，因此進一步瞭解9D7抗體是如何調控細胞的訊息傳遞，進而影響IL-2細胞激素的表現。我們先將9D7抗體和Jurkat細胞共同培養後，再加入phytohemaggl- utinin（PHA）刺激，發現9D7抗體不會改變細胞內鈣離子的濃度。此外，將9D7抗體和Jurkat細胞共同培養24小時後，再加入PHA及phorbol 12-myristate 13-acetate（PMA）刺激細胞，由西方墨點法分析發現，9D7抗體會明顯增加Jurkat細胞中p38及ERK的磷酸化，但對於Akt的磷酸化沒有影響；當先加入p38抑制物SB203580及ERK抑制物PD98059，則發現到實驗組與對照組IL-2蛋白質的產生沒有差異，無法看到原先9D7抗體造成IL-2產生量減少的現象，推測MAPK家族中，p38及ERK的活化對於Jurkat細胞產生IL-2是必須的，而9D7抗體抑制Jurkat細胞分泌IL-2可能經由這兩條路徑。
之前研究發現9D7抗體會抑制PGK-1之酵素活性，而9D7抗體辨認PGK-1的交叉點為酵素作用的催化區，因此推測9D7抗體可能藉由與PGK-1的催化區結合，降低PGK-1的酵素功能，已知PGK-1的缺乏會引起神經錯亂、心智遲緩，所以推測抗雙股DNA抗體對PGK-1的影響可能和SLE病人神經病變的現象有關連。另外，9D7抗體會促進細胞中MAPKs的磷酸化，進而調控細胞激素產生，並促進抗體生成，導致抗體沈積於腎臟中，造成腎臟衰竭。

Anti-dsDNA autoantibodies are not only specific for systemic lupus erythematosus (SLE) but also play an important role in the pathogenesis and activity of this disease. The anti-DNA monoclonal antibodies (anti- DNA mAb) 9D7 derived from lupus-prone mice may cross-react with two protein antigens (35 KDa and 50 KDa) in several cell lines. The 35 KDa protein antigen has been identified as the heterogenous nuclear ribonucleoprotein A2 (hnRNP A2) and its RGG domain is cross-reactive with 9D7. The 50KDa protein antigen has been demonstrated to be phosphoglycerate kinase-1 (PGK-1). However, the region of this protein antigen that interacts with anti-DNA mAb remains unclear. Since PGK-1 contains the catalytic domain I (CDI), nucleotide binding domain (NBD), and catalytic domain II (CDII), four mutants of PGK-1 (PGKΔCDII, PGKΔCDI, PGK-CDI, and PGK-NBD) were expressed and purified. PGK-CDI was demonstrated to be cross-reactive with 9D7 by Western blotting. This finding suggests that arginine is an important component in the region cross-reactive with anti-DNA mAb, since the RGG domain of hnRNPA2 and CDI of PGK-1 are arginine enriched areas.
In our previous studies, 9D7 has been demonstrated to suppress the promoter activity as well as expression of IL-2 gene in Jurkat T cells. After co-culturing Jurkat T cells with 9D7 for 24 h and activating with phytohemagglutinin (PHA) and phorbol 12-myristate 13-acetate (PMA), the levels of phospho-p38 and phospho-ERK in Jurkat T cells significantly increased whereas the level of phosphor-AKT remained unchanged. Moreover, no significant differences in the level of IL-2 were observed in the activated cells co-cultured with 9D7 (experimental group) and IgG2b (control group) by pre-treating the cultures with p38 inhibitor (SB203580) or ERK inhibitor (PD98059). These findings suggest that anti-dsDNA autoantibodies may regulate cytokine secretion by increasing T cell MAPKs phosphorylation and, in turn, trigger the cellular events
associated with SLE.

參考資料
1. Blot zer JW. 1983 Jun. Systemic lupus erythematosus I : historical aspects. Md State Med J. 32:439.
2. Kaposi MH. Neue Beitrage zur Keantiss des. 1872. lupus erythematosus. Arch Dermatol Syphilol 4:36.
3. Osler W.1904. On the visceral manifestations of the erythema group of skin diseases (third paper). Am J Med Sci. 127:1.
4. Jadassohn J. 1904. Lupus erythematosus. In: Mracek F, ed. Handbach der Hautkrakheiten. Wien: Alfrad Holder, 298.
5. Moore JE, Lutz WB. 1955. The natural history of systemic lupus erythematosus: An approach to its sudty through chronic biological false positive reactions. J Chron Dis. 2:297.
6. Friou GJ. 1957. Clinical application of lupus serum nucleoprotein reaction using fluorescent antibody technique. J Clin Invest. 36:890.
7. Tan, E.M. et. Al. 1982. The 1982 Revised Criteria for the Classification of SLE. Arthritis and Rheumatism, 25:1271.
8. Hochberg, M.C. September 1997. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus, Arthritis and Rheumatism, 40:1725.
9. Tan, E.M. 1989. Antinuclear antibodies: Diagnostic markers for autoimmune disease and probes for cell biology. Adv. Immunol. 44:93.
10. Kotzin B.L., O’ Dell, J.R. 1995. Systemic lupus erythematosus. In Samter’s immunologic disease, fifth edition, 667.
11. Ravirajan CT, Rowse L, MacGowan JR, Isenberg DA. 2001. An analysis of clinical disease activity and nepheritis-associated serum autoantibody profiles in patients with SLE: a cross-sectional study. Rheumatology 40:1405.
12. Arnett FC, Reveille JD, Moutsopoulos HM, Georgescu L, Elkon KB. 1996. Ribosomal P. Autoantibodies in SLE. Arthritis Rheum, 39: 1833.
13. Stites, D.P., Terr, A.I., and Parslow T.G. 1997. Medical Immunology, 9th Edition, p459.
14. Vyse, T.J., and Todd, J.A. 1996. Genetic analysis of autoimmune disease. Cell 85:311.
15. Pisetsky, D.S. 1991. Systemic lupus erythematosus. Curr. Opin. Immunol. 3:917.
16. Hauptmann, G., Tappeiner, G., and Schifferli J.A. 1988. Inherited deficiency of the fourth component of human complement. Immunpdef. Rev. 1:3.
17. Harley, J.B., Moser, K.L., Gaffney, P.M., and Behrens, T.W. 1998. The genetics of human systemic lupus erythematosus. Curr.Opin. Immunol. 10:690.
18. Chen, Z., S. B. Koralov, and G. Kelsoe. 2000. Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. J. Exp. Med. 192: 1339.
19. Eliot, M. 2002. Lupus: mysterious disease holds ts secrets tight. Science 26:689.
20. Verthelyi, D. 2001. Sex hormones as immunomodulators in health and disease. Int immunopharmacol. 1:983.
21. Satoh, M., Kumar, A., Kanwar, Y.S. and Reeves, W.H. 1995. Antinuclear antibody production and immune-complex glomerulonephritis in BALB/c mice treated with pristine. Proc. Natl. Acad. Sci. USA 92:10934.
22. James, J.A., Neas, B.R., Moser, K.L., Hall, T., Bruner, G.R., Sestak, A.L. and Harley, J.B. 2001. Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure. Artheitis Rheum. 44:1122.
23. Lahita, R.G. John Wiley & Sons, inc. 1987. Systemic lupus erythematosus.
24. Shlomchil, M.J., Aucoin, A.H., pisetsky, D.S., and Weigert, M.G. 1987. Structure and function of anti-DNA autoantibodies derived from a single autoimmune mouse. Proc. Natl. Acad. Sci. USA 84:9150.
25. Marion, T.N., Krishnan, M.R., Desai, D.D., Jou. N.T., and Tillman, D.M. 1997. Monoclonal anti-DNA antibodies: structure, specificity, and biology. Methods 11:3.
26. O’keefe, T.L., Bandyopadhyay, S., Datta, S.K., and ImanishiKari, T. 1990. Vregion sequences of an idiotypically connected family of pathogenic anti-DNA autoantibodies. J. Immunol. 144:4275.
27. Chan, V.W., Meng, F., Soriano, P., DeFranco, A.L., and Lowell, C.A. 1997. Characterization of the B lymphocyte populations in Lyn- deficient mice and the role of Lyn in signal initiation and downregulation. Immunity 7:69.
28. Theofilopoulos, A.N., and F.J. Dixon. 1985. Murine models of systemic lupus erythematosus. Adv. Immunol. 37:269.
29. Losman, M.J., Fasy, T.M., Novick, K.E., and Monistier, M. 1992. Monoclonal autoantibodies to subnucleosomes from MRL/Mp+/+ mouse: oligoclonality of the response and recognition of a determinant composed of histones H2A, H2B and DNA. J. Immunol. 148:1561.
30. Viard, J.P., Choquette, D., Chabre, H., Slama, F.B., Primo, J., Letrait, M., Venot, A. and Jacob, L. 1992. Anti-histone reactivity in systemic lupus erythematosus sera: a disease activity index linked to the presence of DNA: anti-DNA immune complexes. Autoimmunity 12:61.
31. Marion, T.N., Krishnan, M.R., Desai, D.D., Jou. N.T. and Tillman, D.M. 1997. Monoclonal anti-DNA antibodies: structure, specificity, and biology. Methods 11:3.
32. Sano, H. Imolawa, M., Steinberg, A.D. and Monr
imoto, C. 1983. Accumulaiton of guanine-cytosine-enriched low M.W. DNA fragment in lymphocytes of patients with systemic lupus erythematosus. J. Immunol. 130:187.
33. Gilkeson, G.S., Grudier, J.P., Karounos, D.G., and Pisetsky, D.S. 1989. Induction of anti-dsDNA antibodies in normal mice by immunization with bacterial DNA. J. Immunol. 142:1484.
34. Messina, J.P., Gilkeson, G.S. and Pisetsky, D.S. 1993. The influence of DNA structure on the in vitro stimulation of murine lymphocytes by natural and synthetic polynucleotide antigens. Cellular Immunol. 147:148.
35. Pisetsky, D.S. and Gonzalez, T.C. 1999. The influence of DNA siza on the binding of antibodies to DNA in the sera of normal human sucjects and patients with systemic lupus erythematosus(SLE). Clin. Exp. Immunol. 116:354.
36. Watanabe-Fukunaga, R., C.I. Brannan, N.G. Copeland, N.A. Jenkins and S. Nagata. 1992. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature (Lond). 356:314.
37. Monistier, M. 1997. Autoantibodies to nucleosomes and histone-DNA complexes. Methods. 11:36.
38. Amoura, Z., Chabres, H., Koutouzov, S., Lotton, C., Cabrespines, A., Bach, J.F. and Jacob, L. 1994. Nucleosome-restricted antibodies are detected before anti-dsDNA and/or anti-histone antibodies. Arthritis Rheum. 37:1684.
39. Termaat RM, Assmann KJ, Dijkman HB, van Gompel F, Smeenk RJ, Berden JH. 1992. Anti-DNA antbodies can bind to the glomerulus via two distinct mechanisms. Kidney Int. 42:1363.
40. Sabbaga, J., Line, S.R., Potochjak, P. and Madaio, M.P. 1989. A murine nephritogenic monoclonal anti-DNA autoantibody bonds directly to mouse laminin, the major non-collagenous protein component of the glomerular basement membrane. Eur. J. Immunol. 19:137.
41. Faaber, P., Rijke, T.P., van de putte, L.B., Capel, P.J. and Berden, J.H. 1986. Cross-reactivity of human murine anti-DNA antobodies with heparan sulfate: the major glycosaminoglycan in glomerular basement membranes. J. Clin. Invest. 77:1824.
42. Reichlin, M., Martin, A., Taylor-Albert, E., Tsuzaka, K., Zhang, W., Reichlin, M.W., Koren, E., Ebling, F.M., Taso, B. and Hahn, B.H. 1994. Lupus autoantibodies to native DNA cross-react with the A and D SnRNP polypeptides. J. Clin. Invest. 93:443.
43. Zack, D.J., Yamamoto, K., Wong, A.L., Stempniak, M., French, C. and Weisbart, H. 1995. DNA mimics a self-protein that may be a target for some anti-DNA antibodies in systemic lupus erythematosus. J. Immunol. 154:1987.
44. Puccetti, A., Madaio, M.P. and Bellese, G. 1995. Anti-DNA antibodies bind to DNase I. J. Exp. Med. 181:1797.
45. Tsuzaka, K., Leu, A.K., Frank, M.B., Movafagh, B.F., Koscec, M., Winkler, T.H., Kalden, J.R. and Reichlin, M.1996. Lupus autoantibodies to double-stranded DNA cross-react with ribosomal protein S1. J. Immunol. 156:1668.
46. Deocharan, B., Qing, X., Lichauco, J. and Putterman, C. 2002 α-actinin is a cross-reactive renal target for pathogenic anti-DNA antibodies. J. Immunol. 168:3072.
47. Faaber, P., Rijke, T.P., van de Putte, L.B., Capel, P.J. and Berden, J.H. 1986. Cross-reactivity of human and murine anti-DNA antibodies with heparan sulfate. J. Clin. Invest. 77:1824.
48. Naparstek, Y., Ben-Yehuda, A., Madaio, M.P., Bar-tana, R., Schuger, L., Pizov, G., Neman, Z.V. and Cohen, I.R. 1990. Binding of anti-DNA antibodies and inhibition of glomerulonephritis in MRL-lpr/lpr mice by heparin. Arthritis Rheum. 33:1554.
49. Termaat, R.M., Brinkman. K., van Gompel, F., van den Heuvel, L.P., Veerkamp, J.H., Smeenk, R.J. and Berden, J.H. 1990. Cross-reactivity of monoclonal anti-DNA antibodies with heparan sulfate is mediated via bound DNA/histone complexes. J. Autoimmune. 3:531.
50. Di Valerio, R., Bernstein, K.A., Varghese, E. and Lefkowith, J.B. 1995. Murine lupus glomerulotropic monoclonal antibodies exhibit different specificties but bind via a common mechanism. J. Immunol. 155:2258.
51. Lake, R.A., Morgan, E.A., Henderson, B. and Staines, N.A. 1985. A key role for fibronectin in the sequential binding of native dsDNA and monoclonal anti-DNA antibodies to components of the extracellular matrix: its possible significance in glomerulonephritis. Immunology 54:389.
52. Yanase, K., Smith, R.M., Puccetti, A., Tarett, L. and Madaio, M.P. 1997. Receptor-mediated cellular entry of nuclear localizing anti-DNA amtibodies via myosin. J. Clin. Invest. 100:25.
53. Seddiki, N., Nato,F., Lafaye, P., Amoura, Z., Piette, J.C. and Mazie’. J.C. 2001. Calreticulin, a potential cell surface receptor involved in cell penetrationof anti-DNA antibodies. J. Immunol. 166:6423.
54. Sun K.G., Liu W.T., Tasi C.Y., Tang S.J., Han S.H., Yu C.L. Anti-dsDNA antibodies cross-react with ribosomal P proteins expressed on the surface of glomerular mesangial cells to exert a cytostatc effect. Immunology. 1995. 85:262.
55. K. H. Sun, S. J. Tang, Y. S. Wang, W.J. Lin and R. I. You. Autoantibodies to dsDNA cross-react with the arginine-glycine-rich domain of heterogeneous nuclear ribonucleoprotein A2(hnRNP A2) and promote methylation of hnRNP A2. Rheumatology. 2003. 42:154.
56. Putterman, C., and Diamond, B. 1998. Immunization with a peptide surrogate for double-strand DNA induces autoantibody production and renal immunodlobulin deposition. J. Exp. Med. 188:29.
57. Spatz, L.B., Saenko, V., Iliev, A., Jones, L., Geskin, L., Diamond, B. 1997. Light chain usage in anti-double-strand DNA B cell subsetsL role in cell fate determination. J. Exp. Med. 185:317.
58. Giorgio, L.A., Konstantinov, K.N., Lee. S.C., Hardin, J.A.m Volpe, B.T. and Diamond, B. 2001. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat. Med. 7:1189.
59. Jacob, L., Tron, F., Bach, J.F. and Louvard, D. 1984. A monoclonal anti-DNA antibody also binds to cell-surface protein(s). Proc. Natl. Acad. Sci. USA 81:3843.
60. Jacob, L., Lety, M.A. and Bach, J.F. 1986. Human systemic lupus erythematosus sera contain antibodies against cell-surface protein(s) that share(s) epitope(s) with DNA. Proc. Natl. Acad. Sci. USA 83:6970.
61. Raz, E., Ben Bassat, H., Davidi, T., Shlomai, Z. and Eilat, D. 1993. Cross-reactions of anti-DNA autoantibodies with cell surface proteins. Eur. J. Immunol. 23:383.
62. Gaynor, B., Putterman, C., Valadon, P., Spatz, L., Scharrff, M.D. and Diamond, B. 1997. Peptide inhibitory of glomerular deposition of an anti-DNA antibody. Proc. Natl. Acad. Sci. USA 94:1955.
63. Sibille, P., Ternynck, T., Nato, F., Buttin, G., Strosberg D. and Avrameas, A. 1997. Mimotopes of polyreactive anti-DNA antibodies identified using phage-display peptide libraries. Eur. J. Immunol. 27:1221.
64. Koren, E., Koscec, M., Wolfson-Reichlin M. 1995. Murine and human antibodies to native DNA that cross-react with the A and D SnRNP polypeptides cause direct injury of cultured kidney cells. J. Immunol. 154:4857.
65. Koutouzov, S., A. Cabrespines, Z. Amoura, H. Chabre, C. Lotton, and J. F. Bach. 1996. Binding of nucleosomes to a cell surface receptor redistribution and endocytosis in the presence of lupus antibodies. Eur. J. Immunol. 26:472.
66. ALEXANDRE AVRAMEAS, The′RE‵SE TERNYNCK, FARI-DABANO NATO, GE RARD BUTTIN and STRATIS AVRAMEAS. 1998. Polyreactive anti-DNA monoclonal antibodies and a derived peptide as vectors for the intracytoplasmic and intranuclear translocation of macromolecules. Proc. Natl. Acad. Sci. USA 95:5601.
67. I.-Yih Huang, Cori D. Welch and Akira Yoshida. 1980. Complete Amino Acid Sequence of Human Phosphoglycerate Kinase. J. Biol. Chem. 255:6412.
68. R. D. Banks, C. C. F. Blake, P. R. Evans, R. Haser & D. W. Rice. 1979. Sequence, structure and activity of Phosphoglycerate Kinase : a possible hinge-bending enzyme. Nature 279:773.
69. Michelson, A.M., Blake, C.C., Evans, S.T. and Orkin, S.H. 1985. Structure of the human Phosphoglycerate kinase gene and the intron-mediated evolution and dispersal of the nucleotide-binding domain. Proc. Natl. Avad. Sci. U.S.A. 82:6965.
70. Akira Yoshida, Thomas W. Twele, Vibha Dave, Ernest Bwutler. 1995. Molecular Abnormality of a Phosphoglycerate Kinase Variant(PGK- Alabama). Blood Cells, Molecules, and Diseases. 21:179.
71. Scopes, R.K. 1973. In The Enzyme, ed. Boyer, P.D. (Academic, New York), 1.8:335.
72. Lay, A.J., Jiang, X.M., Kisker, O., Flynn, E., Underwood, A., Cordron, R. And Hogg, P.J. 2000. Phosphoglycerate kinase acts in tumor angiogenesis as a disulphide reductase. Nature 408:869.
73. Vishwanatha, J.K., Jindal, H.K. and Davis, R.G. 1992. The role of primer recognition proteins in DNA replication: association with nuclear matrix in HeLa cells. J. Cell. Sci. 101:25.
74. Popanda, O., Fox, G. and Thielmann, H. W. 1998. Modulation of DNA polymerases alpha, delta and epsilon by lactate dehydrogenase and 3-phosphoglycerate kinase. Biochim. Biophys. Acta. 1397:102.
75. Odilia Popanda, Gabriele Fox, Heinz Walter Thielmann. 1998. Modulation of DNA polymer ase α,δandε by lactate dehydrogenase and 3-phosphoglycerate kinase. Biochemica et Biophysica Acta. 1397:102.
76. Ogino, T., Iwama, M., Kinouchi, J., Shibagaki, Y., Tsukamoto, T. and Mizumoto, K. 1999. Involvement of a cellular glycolytic enzyme, Phosphoglycerate kinase, in Sendai virus transcription. J. Biol. Chem. 274:35999.
77. Paron I, D’Elia’ A, D’Ambrosio C, Scaloni A, D’Aurizio F, Proscott A, Damante G, Tell G. 2004. A proteomic approach to identify early molecular targets of oxidative strss in human epithelial lens cells. Biochem J. 378:929.
78. Valentine, W.H., Hsiah, H-S., Paglia, D.E., etc. 1969. Chromosome aberrations in 2159 consecutive newborn babies. N. Engl. J. Med. 280:528.
79. Adra CN. Et al. 1987. Cloning and exoression of the mouse pgk-1 gene and the nucleotide sequence of its promoter. Gene 60:65
80. Kramer J.M. and Erickson, R.P, 1981. Developmental program of PGK-1 and PGK-2 isozymes in spermatogenic cells of the mouse: specific activities and rates of synthesis. Dev. Biol. 87:37.
81. VandeBerg JL. 1985. The Phosphoglycerate kinase isozyme system in mammals: biochemical, genetic, developmental, and evolutionary aspects. Isozymes Curr Top Biol Med Res. 12:133.
82. Karus AP, Langston MF Jr, Lynch BL. 1968. Red cell Phosphoglycerate kinase deficiency. A new cause of non-spherocytic hemolytic anemia. Biochem Biophys Res Commun. 30:173.
83. Dimaurso. S, Dalakas. M, Miranada, A. 1981. Phosphoglycerate kinase deficiency: a new case of recurrent myoglobinurea. Trans Am Neurol Soc. 106:202.
84. Fujii, H.; Kanno, H.; Hirono, A.; Shiomura, T.; Miwa, S. A single amino acid substitution (157gly-to-val) in a phosphoglycerate kinase variant (PGK Shizuoka) associated with chronic hemolysis and myoglobinuria. Blood. 1992. 79: 1582.
85. Davis, R.J. MAPKs: new JNK expands the group. Trends Biochem. Sci. 1994. 19:470.
86. Minden A., A. Lin, M. McMahon, C. Lange-Carter, B. Derijard, R. J. Davis, G. L. Johnson, and M. Karin. Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science 266:1719.
87. Natoil, G., A. Costanzo, A. Ianni, D. J. Templeton, J. R. Woodgett, C. Balsano and M. Levrero. Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway. 1997. Science 275:200.
88. Whitmarsh, A. J., P. Sjore, A. D. Sharrocks, and R. J. Davis. Integration of MAP kinase signal transduction pathways at the serum response element. 1995. Science 269:403.
89. Stokoe D, Macdonald, SG , Cadwallader K, Symons, M, Hancock JF. Activation of Raf as a result of recuitment to the plasma membrane. Science 1994. 264:1463.
90. Frödin M, Gammeltoft S. Role and regulation of 90KDa ribosomal S6 kinase (RSK) in signal transduction. Mol Cell Endocrino 1999. 151:65.
91. Seger R, Krebs EG.The MAPK signaling cascade. FASEB J 1995. 9:726.
92. Pages G, Lenormand P, L'' Allemain G, Chambard J C, Meloche S, Pouyssegur J. Mitogen-activated protein kinase p42MAPK and p44MAPK are required for fibroblastProliferation. Pro Natl Acad Sci USA 1993. 90:8319.
93. Ichijo H. From receptors to stress-activated MAP Kinase. Oncogene 1999. 18:6087.
94. Goh KC, Haque SJ, William BR. p38 MAP Kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons. EMBO J 1999. 18:5601.
95. Wang XZ, Ron D. stress-indeced phosphorylation and activatin of the transcription factor CHOP (GADD153) by p38 MAP kinase. Science 1996. 272:1347.
96. Molnar A, Theodoras A M, Zon L I, Kyriakis J M. Cdc42Hs, but not Rac 1, inhibits serum-stimulated cell cycle progressin at G1/S through a mechanism requiring p38/RK. J Biol Chem 1997. 272:13229.
97. Takenaka K, Mcriguchi T, Nishida E. Activation of the protein kinase p38 in the spindle assembly checkpoint and mitotic arrest. Science 1998. 280:599.
98. Nebread AR. p38 MAP kinase: beyond the stress response. TIBS 2000. 25:257.
99. Cantley, L. C., and B. G. Neel. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. 1999. Proc. Natl. Acad. Sci. USA 96:4240.
100. Chan, T. O., S. E. Rittenhouse, and P. N. Tsichlis. Akt/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide- dependent phosphorylation. Annu. Rev. Biochem. 1999. 68:965.
101. Coffer, P. J., J. Jin, and J. R. Woodgett. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. 1998. Biochem. J. 335:1.
102. Datta, S. R., A. Brunet, and M. E. Greenberg. Cellular survival: a play in three Akts. Genes Dev. 1999.13:2905.
103. Richard A. G., Thomas J. K., Barbara A. O. Kuby Immunology. 14th:308.
104. Dept. HEW-PHS. Quantitation and Functional Assay of T and B cells. In Immunology Series Bo.8 Procedual Guide. p11.
105. A Weiss, RL Wiskocil, and JD Stobo. The role of T3 surface molecules in the activation of human T cells: a two-stimulus requirement for IL 2 production reflects events occurring at a pre-translational level J. Immunol. 1984. 133:123.
106. Baosheng Ge, Olga Li, Phillip Wilder, Angie Rizzino, and Timothy W. McKeithan. NF- B Regulates BCL3 Transcription in T Lymphocytes Through an Intronic Enhancer J. Immunol. 2003. 171:4210.
107. 1 Kammer, G.M., Tsokos, G.C. Lupus:Molecular and Cellular Pathogenesis. 1999 p.1.
108. Tsokos, G.C. and Liossis, S.N. Immune cell signaling defects in lupus: activation, anergy and death. Immunol. 1999. Today 20, 119.
109. Yui MA, Brissette WH, Brennan DC, Wuthrich RP, Kelley VR: Increased macrophage colony-stimulating factor in neonatal and adult autoimmune MRL-lpr mice. Am J Patho. 1991. 139: 255.
110. Yokoyama H, Kreft B, Kelley VR: Biphasic increase in circulating and renal TNF-α in MRL-lpr mice with differing regulatory mechanisms. Kidney Int. 1995. 47: 122.
111. Wada T, Naito T, Griffiths RS, Coffman TM, Kelley VR: Systemic autoimmune nephritogenic components induce CSF-1 and TNF-α in MRL kidneys. Kidney Int. 1997. 52: 934.
112. Nick JA, Avdi NJ, Young SK, Lehman LA, McDonald PP, Frasch SC, Billstrom MA, Henson PM, Johnson GL, Worthen GS: Selective activation and functional significance of p38 alpha mitogen-activated protein kinase in lipopolysaccharide- stimulated neutrophils. J Clin Invest. 1999. 103: 851.
113. Campell KS: Signal transduction from the B cell antigen-receptor. Curr Opin Immunol. 1999. 3: 256.
114. Luan H. Y. Cognate antigens and effects on cytokine expression of anti-DNA monoclonal autoantibody. 2003. Master Thesis.
115. Kotzin B.L. Systemic lupus erythematosus. Cell 85:303.
116. Koffler D., Schur P.H. , Kunkel H.G. Immunological studies concering the nephritis of systemic lupus erythematosus. J. Exp. Med. 126:607.
117. Lambert P.H., Dixon F. J. Pathogenesis of the glomerulonephritis of NZB/W mice. J. Exp. Med. 127:507.
118. Weinberg JB. Nitric oxide as an inflammatory mediator in autoimmune MRL-lpr/pr mice. Environ. Health. Perspect. 1998. 106:1131.
119. Huang F.P., Feng G.J., Lindop G., Stott D.I. The role of IL-12 and nitric oxide in the development of aponraneous autoimmune desease in MRL inverted question markMP-lpr inverted question mice. J. Exp. Med. 1996. 183:1447.
120. Refaeli, Y., L. Van Parijs, C. A. London, J. Tschopp, A. K. Abbas. 1998. Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity 8:615.
121. Rovin GH, Wilmer WA, Danne M, Dickerso JA, Dixon CL, Lu L. The mitogen-activated protein kinase p38 is necessary for interleukin 1β-induced monocytes chemoattractant protein 1 expression by human mesangial cells. Cytokine. 1999. 11:118.
122. Ganju PK, Dutt P, Wu L, Newman W, Avraham H. β-chemokine receptor CCR5 signals via the novel tyrosine kinase RAFTK. Blood 1998. 91:791.
123. Schett G, Tohidast-Akrad M, Steiner CW, Bitzan P, Steiner G. Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal regulated kinases, c-JUN N terminal kinases, and p38 mitogen activated protein kinase. In sinovial tissue and cells in rheumatoid arthritis. Arthritis Rheum. 2000. 43:2501.
124. Yui MA, Brissette WH, Kelly VR, Wuthrich RP, Bernan DC. Increased macrophage colony-stimulating factor in neonatal and adult autoimmune KRL-lpr mice. Am J Patho. 1991. 139:255.
125. Yokoyama H, Kreft B, Kelley VR. Biphasic increase in circulating and renal TNF-α in MRL-lpr mice with differing regulatory mechanisms. Kidney Int. 1995. 47:122.
126. Wada T, Naito T, Griffiths RS, Coffman TM, Kelley VR. Systemic autoimmune nephritogenic components induce CSF-1 and TNF-αin MRL kidneys. Kidney Int. 1997. 52:934.
127. Nick JA, Avdi NJ, Young SK, Lehman LA, Johnson GL, Worthen GS. Selective activation and functional significance of p38 alpha mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophis. J Clin Invest. 1999. 103:851.
128. Kengo F, Noruichi S, Hitoshi Y, Ken-ichi K. p38 Mitogen-Activated Protein kinase Contributes to Autoimmune Renal Injury in MRL-Faslpr mice. J Am Soc Nephrol. 2003. 14:57.
129. Lowenthal, J. W., R. H. Zubler, M. Nabholz, H. R. MacDonald. 1985. Similarities between interleucin-2 receptor number and affinity on activated B and T lymphocytes. Nature 315:669.
130. Schwartz, R. H.. 1997. T cell clonal anergy. Curr. Opin. Immunol. 9:351.
131. Powell, D. J., C. G. Lerner, G. R. Ewoldt, R. H. Schwartz. 1999. The -180 site of the IL-2 promoter is the target of CREB/CREM binding in T cell anergy. J. Immunol. 163:6631.
132. Wong, H. K., G. M. Kammer, G. Dennis, G. C. Tsokos. 1999. Abnormal NF- B activity in T lymphocytes from patients with systemic lupus erythematosus is associated with decreased p65-RelA protein expression. J. Immunol. 163:1682.
133. Powell, J. D., C. G. Lerner, G. R. Ewoldt, R. H. Schwartz. 1999. The -180 site of the IL-2 promoter is the target of CREB/CREM binding in T cell anergy. J. Immunol. 163:6631.
134. Klaus T, Yuang-Taung J, Mark F. G., Madhusoodana P. N., George C.T. Antisense Cyclic Adenosine 5''-Monophosphate Response Element Modulator Up-Regulates IL-2 in T Cells from Patients with Systemic Lupus Erythematosus. J Immunology. 2002. 169: 4147-4152.
135. Trivier, E., De Cesare, D., Jacquot, S., Pannetier, S., Zackai, E., Young, I., Mandel, J. L., Sassone-Corsi, P. and Hanauer, A. (1996) Mutations in the kinase RSK2 associated with Coffin-Lowry Syndrome. Nature 384, 567.
136. Deak, M., A. D. Clifton, L. M. Lucocq, and D. R. Alessi. 1998. Mitogen- and stress-activated protein kinase-1 (MSK-1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J. 17:4426.
137. de Groot, R. P., L. M. Ballow, and P. Sassone-Corsi. 1994. Positive regulation of the cAMP-responsive activator CREM by the p70 S6 kinase: an alternative route to mitogen-induced gene expression. Cell 79:81.