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標題: 腫瘤抑制基因HLJ1經由類鐸受體二之訊息傳遞路徑調控介白素八之表現
Tumor Suppressor HLJ1 Regulates Interleukin-8 Expression through Toll-like Receptor 2 Pathway
作者: 蔡銘珈
Tsai, Ming-Chia
關鍵字: heat shock protein;熱休克蛋白;toll like receptor;類鐸受體
出版社: 生物醫學研究所
引用: 參考文獻 Abbott, S.L., Waddington, M., Lindquist, D., Ware, J., Cheung, W., Ely, J. and Janda, J.M. (2005) Description of Campylobacter curvus and C. curvus-like strains associated with sporadic episodes of bloody gastroenteritis and Brainerd''s diarrhea. J Clin Microbiol, 43, 585-588. Akira, S. and Takeda, K. (2004) Toll-like receptor signalling. Nat Rev Immunol, 4, 499-511. Akira, S., Takeda, K. and Kaisho, T. (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol, 2, 675-680. Anthony, L.S., Wu, H., Sweet, H., Turnnir, C., Boux, L.J. and Mizzen, L.A. (1999) Priming of CD8+ CTL effector cells in mice by immunization with a stress protein-influenza virus nucleoprotein fusion molecule. Vaccine, 17, 373-383. Asea, A., Kraeft, S.K., Kurt-Jones, E.A., Stevenson, M.A., Chen, L.B., Finberg, R.W., Koo, G.C. and Calderwood, S.K. (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med, 6, 435-442. Asea, A., Rehli, M., Kabingu, E., Boch, J.A., Bare, O., Auron, P.E., Stevenson, M.A. and Calderwood, S.K. (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem, 277, 15028-15034. Balkwill, F. and Mantovani, A. (2001) Inflammation and cancer: back to Virchow? Lancet, 357, 539-545. Basu, S., Binder, R.J., Suto, R., Anderson, K.M. and Srivastava, P.K. (2000) Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol, 12, 1539-1546. Beere, H.M., Wolf, B.B., Cain, K., Mosser, D.D., Mahboubi, A., Kuwana, T., Tailor, P., Morimoto, R.I., Cohen, G.M. and Green, D.R. (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol, 2, 469-475. Beg, A.A. (2002) Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol, 23, 509-512. Belvin, M.P. and Anderson, K.V. (1996) A conserved signaling pathway: the Drosophila toll-dorsal pathway. Annu Rev Cell Dev Biol, 12, 393-416. Beutler, B. (2004) Inferences, questions and possibilities in Toll-like receptor signalling. Nature, 430, 257-263. Binder, R.J., Vatner, R. and Srivastava, P. (2004) The heat-shock protein receptors: some answers and more questions. Tissue Antigens, 64, 442-451. Bork, P., Sander, C., Valencia, A. and Bukau, B. (1992) A module of the DnaJ heat shock proteins found in malaria parasites. Trends Biochem Sci, 17, 129. Botzler, C., Ellwart, J., Gunther, W., Eissner, G. and Multhoff, G. (1999) Synergistic effects of heat and ET-18-OCH3 on membrane expression of hsp70 and lysis of leukemic K562 cells. Exp Hematol, 27, 470-478. Bowie, A. and O''Neill, L.A. (2000) The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for pro-inflammatory interleukins and microbial products. J Leukoc Biol, 67, 508-514. Campos, M.A., Almeida, I.C., Takeuchi, O., Akira, S., Valente, E.P., Procopio, D.O., Travassos, L.R., Smith, J.A., Golenbock, D.T. and Gazzinelli, R.T. (2001) Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite. J Immunol, 167, 416-423. Caplan, A.J., Cyr, D.M. and Douglas, M.G. (1993) Eukaryotic homologues of Escherichia coli dnaJ: a diverse protein family that functions with hsp70 stress proteins. Mol Biol Cell, 4, 555-563. Cheetham, M.E. and Caplan, A.J. (1998) Structure, function and evolution of DnaJ: conservation and adaptation of chaperone function. Cell Stress Chaperones, 3, 28-36. Chow, J.C., Young, D.W., Golenbock, D.T., Christ, W.J. and Gusovsky, F. (1999) Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem, 274, 10689-10692. Cyr, D.M., Lu, X. and Douglas, M.G. (1992) Regulation of Hsp70 function by a eukaryotic DnaJ homolog. J Biol Chem, 267, 20927-20931. Davis, A.R., Alevy, Y.G., Chellaiah, A., Quinn, M.T. and Mohanakumar, T. (1998) Characterization of HDJ-2, a human 40 kD heat shock protein. Int J Biochem Cell Biol, 30, 1203-1221. Deiters, U., Gumenscheimer, M., Galanos, C. and Muhlradt, P.F. (2003) Toll-like receptor 2- and 6-mediated stimulation by macrophage-activating lipopeptide 2 induces lipopolysaccharide (LPS) cross tolerance in mice, which results in protection from tumor necrosis factor alpha but in only partial protection from lethal LPS doses. Infect Immun, 71, 4456-4462. Di Carlo, E., Forni, G., Lollini, P., Colombo, M.P., Modesti, A. and Musiani, P. (2001) The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood, 97, 339-345. Dobrovolskaia, M.A., Medvedev, A.E., Thomas, K.E., Cuesta, N., Toshchakov, V., Ren, T., Cody, M.J., Michalek, S.M., Rice, N.R. and Vogel, S.N. (2003) Induction of in vitro reprogramming by Toll-like receptor (TLR)2 and TLR4 agonists in murine macrophages: effects of TLR "homotolerance" versus "heterotolerance" on NF-kappa B signaling pathway components. J Immunol, 170, 508-519. Dybdahl, B., Wahba, A., Lien, E., Flo, T.H., Waage, A., Qureshi, N., Sellevold, O.F., Espevik, T. and Sundan, A. (2002) Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation, 105, 685-690. Gehrmann, M., Marienhagen, J., Eichholtz-Wirth, H., Fritz, E., Ellwart, J., Jaattela, M., Zilch, T. and Multhoff, G. (2005) Dual function of membrane-bound heat shock protein 70 (Hsp70), Bag-4, and Hsp40: protection against radiation-induced effects and target structure for natural killer cells. Cell Death Differ, 12, 38-51. Gehrmann, M., Pfister, K., Hutzler, P., Gastpar, R., Margulis, B. and Multhoff, G. (2002) Effects of antineoplastic agents on cytoplasmic and membrane-bound heat shock protein 70 (Hsp70) levels. Biol Chem, 383, 1715-1725. Gething, M.J. and Sambrook, J. (1992) Protein folding in the cell. Nature, 355, 33-45. Hashimoto, C., Hudson, K.L. and Anderson, K.V. (1988) The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell, 52, 269-279. Hayashi, F., Smith, K.D., Ozinsky, A., Hawn, T.R., Yi, E.C., Goodlett, D.R., Eng, J.K., Akira, S., Underhill, D.M. and Aderem, A. (2001) The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature, 410, 1099-1103. Helmbrecht, K., Zeise, E. and Rensing, L. (2000) Chaperones in cell cycle regulation and mitogenic signal transduction: a review. Cell Prolif, 33, 341-365. Hendrick, J.P. and Hartl, F.U. (1993) Molecular chaperone functions of heat-shock proteins. Annu Rev Biochem, 62, 349-384. Hickman, H.D., Luis, A.D., Buchli, R., Few, S.R., Sathiamurthy, M., VanGundy, R.S., Giberson, C.F. and Hildebrand, W.H. (2004) Toward a definition of self: proteomic evaluation of the class I peptide repertoire. J Immunol, 172, 2944-2952. Hoe, K.L., Won, M., Chung, K.S., Jang, Y.J., Lee, S.B., Kim, D.U., Lee, J.W., Yun, J.H. and Yoo, H.S. (1998) Isolation of a new member of DnaJ-like heat shock protein 40 (Hsp40) from human liver. Biochim Biophys Acta, 1383, 4-8. Hoebe, K., Du, X., Georgel, P., Janssen, E., Tabeta, K., Kim, S.O., Goode, J., Lin, P., Mann, N., Mudd, S., Crozat, K., Sovath, S., Han, J. and Beutler, B. (2003) Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature, 424, 743-748. Holtmann, H., Winzen, R., Holland, P., Eickemeier, S., Hoffmann, E., Wallach, D., Malinin, N.L., Cooper, J.A., Resch, K. and Kracht, M. (1999) Induction of interleukin-8 synthesis integrates effects on transcription and mRNA degradation from at least three different cytokine- or stress-activated signal transduction pathways. Mol Cell Biol, 19, 6742-6753. Hornung, V., Rothenfusser, S., Britsch, S., Krug, A., Jahrsdorfer, B., Giese, T., Endres, S. and Hartmann, G. (2002) Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol, 168, 4531-4537. Jolly, C. and Morimoto, R.I. (2000) Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J Natl Cancer Inst, 92, 1564-1572. Jonjic, N., Peri, G., Bernasconi, S., Sciacca, F.L., Colotta, F., Pelicci, P., Lanfrancone, L. and Mantovani, A. (1992) Expression of adhesion molecules and chemotactic cytokines in cultured human mesothelial cells. J Exp Med, 176, 1165-1174. Kaltschmidt, C., Kaltschmidt, B., Neumann, H., Wekerle, H. and Baeuerle, P.A. (1994) Constitutive NF-kappa B activity in neurons. Mol Cell Biol, 14, 3981-3992. Kao, Y.R., Shih, J.Y., Wen, W.C., Ko, Y.P., Chen, B.M., Chan, Y.L., Chu, Y.W., Yang, P.C., Wu, C.W. and Roffler, S.R. (2003) Tumor-associated antigen L6 and the invasion of human lung cancer cells. Clin Cancer Res, 9, 2807-2816. Kawanishi, K., Shiozaki, H., Doki, Y., Sakita, I., Inoue, M., Yano, M., Tsujinaka, T., Shamma, A. and Monden, M. (1999) Prognostic significance of heat shock proteins 27 and 70 in patients with squamous cell carcinoma of the esophagus. Cancer, 85, 1649-1657. Korbelik, M., Sun, J. and Cecic, I. (2005) Photodynamic therapy-induced cell surface expression and release of heat shock proteins: relevance for tumor response. Cancer Res, 65, 1018-1026. Kumaraguru, U., Pack, C.D. and Rouse, B.T. (2003) Toll-like receptor ligand links innate and adaptive immune responses by the production of heat-shock proteins. J Leukoc Biol, 73, 574-583. Lancaster, G.I. and Febbraio, M.A. (2005) Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J Biol Chem, 280, 23349-23355. Langer, T., Lu, C., Echols, H., Flanagan, J., Hayer, M.K. and Hartl, F.U. (1992) Successive action of DnaK, DnaJ and GroEL along the pathway of chaperone-mediated protein folding. Nature, 356, 683-689. Leek, R.D., Hunt, N.C., Landers, R.J., Lewis, C.E., Royds, J.A. and Harris, A.L. (2000) Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J Pathol, 190, 430-436. Li, C., Shintani, S., Terakado, N., Nakashiro, K. and Hamakawa, H. (2002) Infiltration of tumor-associated macrophages in human oral squamous cell carcinoma. Oncol Rep, 9, 1219-1223. Liberek, K., Skowyra, D., Zylicz, M., Johnson, C. and Georgopoulos, C. (1991) The Escherichia coli DnaK chaperone, the 70-kDa heat shock protein eukaryotic equivalent, changes conformation upon ATP hydrolysis, thus triggering its dissociation from a bound target protein. J Biol Chem, 266, 14491-14496. Lohmann, C., Eggers-Schumacher, G., Wunderlich, M. and Schoffl, F. (2004) Two different heat shock transcription factors regulate immediate early expression of stress genes in Arabidopsis. Mol Genet Genomics, 271, 11-21. Maeda, Y., Pakdaman, K., Nomura, T., Doi, S. and Sato, S. (1998) Reduction of a model for an Onchidium pacemaker neuron. Biol Cybern, 78, 265-276. Mariani, E., Meneghetti, A., Neri, S., Ravaglia, G., Forti, P., Cattini, L. and Facchini, A. (2002) Chemokine production by natural killer cells from nonagenarians. Eur J Immunol, 32, 1524-1529. Medzhitov, R. (2001) Toll-like receptors and innate immunity. Nat Rev Immunol, 1, 135-145. Meier, A., Kirschning, C.J., Nikolaus, T., Wagner, H., Heesemann, J. and Ebel, F. (2003) Toll-like receptor (TLR) 2 and TLR4 are essential for Aspergillus-induced activation of murine macrophages. Cell Microbiol, 5, 561-570. Mukaida, N., Mahe, Y. and Matsushima, K. (1990) Cooperative interaction of nuclear factor-kappa B- and cis-regulatory enhancer binding protein-like factor binding elements in activating the interleukin-8 gene by pro-inflammatory cytokines. J Biol Chem, 265, 21128-21133. Multhoff, G. and Botzler, C. (1998) Heat-shock proteins and the immune response. Ann N Y Acad Sci, 851, 86-93. Muzio, M., Bosisio, D., Polentarutti, N., D''Amico, G., Stoppacciaro, A., Mancinelli, R., van''t Veer, C., Penton-Rol, G., Ruco, L.P., Allavena, P. and Mantovani, A. (2000) Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol, 164, 5998-6004. Nicchitta, C.V. (2003) Re-evaluating the role of heat-shock protein-peptide interactions in tumour immunity. Nat Rev Immunol, 3, 427-432. Nishie, A., Ono, M., Shono, T., Fukushi, J., Otsubo, M., Onoue, H., Ito, Y., Inamura, T., Ikezaki, K., Fukui, M., Iwaki, T. and Kuwano, M. (1999) Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin Cancer Res, 5, 1107-1113. Ohashi, K., Burkart, V., Flohe, S. and Kolb, H. (2000) Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol, 164, 558-561. Ohtsuka, K. and Hata, M. (2000) Molecular chaperone function of mammalian Hsp70 and Hsp40--a review. Int J Hyperthermia, 16, 231-245. Ohtsuka, K., Utsumi, K.R., Kaneda, T. and Hattori, H. (1993) Effect of ATP on the release of hsp 70 and hsp 40 from the nucleus in heat-shocked HeLa cells. Exp Cell Res, 209, 357-366. Palleros, D.R., Reid, K.L., Shi, L. and Fink, A.L. (1993) DnaK ATPase activity revisited. FEBS Lett, 336, 124-128. Parkin, D.M., Pisani, P. and Ferlay, J. (1999) Global cancer statistics. CA Cancer J Clin, 49, 33-64, 31. Parsell, D.A. and Lindquist, S. (1993) The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Annu Rev Genet, 27, 437-496. Polverini, P.J. and Leibovich, S.J. (1984) Induction of neovascularization in vivo and endothelial proliferation in vitro by tumor-associated macrophages. Lab Invest, 51, 635-642. Quintana, F.J., Carmi, P., Mor, F. and Cohen, I.R. (2003) DNA fragments of the human 60-kDa heat shock protein (HSP60) vaccinate against adjuvant arthritis: identification of a regulatory HSP60 peptide. J Immunol, 171, 3533-3541. Quintana, F.J. and Cohen, I.R. (2005) Heat shock proteins as endogenous adjuvants in sterile and septic inflammation. J Immunol, 175, 2777-2782. Rico, A.I., Girones, N., Fresno, M., Alonso, C. and Requena, J.M. (2002) The heat shock proteins, Hsp70 and Hsp83, of Leishmania infantum are mitogens for mouse B cells. Cell Stress Chaperones, 7, 339-346. Ritossa, P. (1962) [Problems of prophylactic vaccinations of infants.]. Riv Ist Sieroter Ital, 37, 79-108. Robert, J. (2003) Evolution of heat shock protein and immunity. Dev Comp Immunol, 27, 449-464. Robert, J., Gantress, J., Rau, L., Bell, A. and Cohen, N. (2002) Minor histocompatibility antigen-specific MHC-restricted CD8 T cell responses elicited by heat shock proteins. J Immunol, 168, 1697-1703. Saito, K., Katsuragi, H., Mikami, M., Kato, C., Miyamaru, M. and Nagaso, K. (1997) Increase of heat-shock protein and induction of gamma/delta T cells in peritoneal exudate of mice after injection of live Fusobacterium nucleatum. Immunology, 90, 229-235. Schett, G., Metzler, B., Kleindienst, R., Amberger, A., Recheis, H., Xu, Q. and Wick, G. (1999) Myocardial injury leads to a release of heat shock protein (hsp) 60 and a suppression of the anti-hsp65 immune response. Cardiovasc Res, 42, 685-695. Silver, P.A. and Way, J.C. (1993) Eukaryotic DnaJ homologs and the specificity of Hsp70 activity. Cell, 74, 5-6. Slack, J.L., Schooley, K., Bonnert, T.P., Mitcham, J.L., Qwarnstrom, E.E., Sims, J.E. and Dower, S.K. (2000) Identification of two major sites in the type I interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways. J Biol Chem, 275, 4670-4678. Soti, C., Nagy, E., Giricz, Z., Vigh, L., Csermely, P. and Ferdinandy, P. (2005) Heat shock proteins as emerging therapeutic targets. Br J Pharmacol, 146, 769-780. Sreedhar, A.S., Nardai, G. and Csermely, P. (2004) Enhancement of complement-induced cell lysis: a novel mechanism for the anticancer effects of Hsp90 inhibitors. Immunol Lett, 92, 157-161. Srivastava, P. (2002a) Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu Rev Immunol, 20, 395-425. Srivastava, P. (2002b) Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol, 2, 185-194. Srivastava, P.K., DeLeo, A.B. and Old, L.J. (1986) Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc Natl Acad Sci U S A, 83, 3407-3411. Strieter, R.M., Polverini, P.J., Kunkel, S.L., Arenberg, D.A., Burdick, M.D., Kasper, J., Dzuiba, J., Van Damme, J., Walz, A., Marriott, D. and et al. (1995) The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem, 270, 27348-27357. Teshima, S., Rokutan, K., Takahashi, M., Nikawa, T. and Kishi, K. (1996) Induction of heat shock proteins and their possible roles in macrophages during activation by macrophage colony-stimulating factor. Biochem J, 315 ( Pt 2), 497-504. Torisu, H., Ono, M., Kiryu, H., Furue, M., Ohmoto, Y., Nakayama, J., Nishioka, Y., Sone, S. and Kuwano, M. (2000) Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: possible involvement of TNFalpha and IL-1alpha. Int J Cancer, 85, 182-188. Tsai, M.F., Wang, C.C., Chang, G.C., Chen, C.Y., Chen, H.Y., Cheng, C.L., Yang, Y.P., Wu, C.Y., Shih, F.Y., Liu, C.C., Lin, H.P., Jou, Y.S., Lin, S.C., Lin, C.W., Chen, W.J., Chan, W.K., Chen, J.J. and Yang, P.C. (2006) A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma. J Natl Cancer Inst, 98, 825-838. Tsung, K., Dolan, J.P., Tsung, Y.L. and Norton, J.A. (2002) Macrophages as effector cells in interleukin 12-induced T cell-dependent tumor rejection. Cancer Res, 62, 5069-5075. Udono, H. and Srivastava, P.K. (1993) Heat shock protein 70-associated peptides elicit specific cancer immunity. J Exp Med, 178, 1391-1396. Udono, H. and Srivastava, P.K. (1994) Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, hsp90, and hsp70. J Immunol, 152, 5398-5403. Vabulas, R.M., Ahmad-Nejad, P., Ghose, S., Kirschning, C.J., Issels, R.D. and Wagner, H. (2002a) HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem, 277, 15107-15112. Vabulas, R.M., Braedel, S., Hilf, N., Singh-Jasuja, H., Herter, S., Ahmad-Nejad, P., Kirschning, C.J., Da Costa, C., Rammensee, H.G., Wagner, H. and Schild, H. (2002b) The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. J Biol Chem, 277, 20847-20853. Wallin, R.P., Lundqvist, A., More, S.H., von Bonin, A., Kiessling, R. and Ljunggren, H.G. (2002) Heat-shock proteins as activators of the innate immune system. Trends Immunol, 23, 130-135. Wang, C.C., Tsai, M.F., Hong, T.M., Chang, G.C., Chen, C.Y., Yang, W.M., Chen, J.J. and Yang, P.C. (2005) The transcriptional factor YY1 upregulates the novel invasion suppressor HLJ1 expression and inhibits cancer cell invasion. Oncogene, 24, 4081-4093. Wang, X.Y., Kazim, L., Repasky, E.A. and Subjeck, J.R. (2001) Characterization of heat shock protein 110 and glucose-regulated protein 170 as cancer vaccines and the effect of fever-range hyperthermia on vaccine activity. J Immunol, 166, 490-497. Yano, M., Naito, Z., Tanaka, S. and Asano, G. (1996) Expression and roles of heat shock proteins in human breast cancer. Jpn J Cancer Res, 87, 908-915. Yuan, A., Chen, J.J., Yao, P.L. and Yang, P.C. (2005) The role of interleukin-8 in cancer cells and microenvironment interaction. Front Biosci, 10, 853-865. Zanin-Zhorov, A., Nussbaum, G., Franitza, S., Cohen, I.R. and Lider, O. (2003) T cells respond to heat shock protein 60 via TLR2: activation of adhesion and inhibition of chemokine receptors. Faseb J, 17, 1567-1569. Zanin-Zhorov, A., Tal, G., Shivtiel, S., Cohen, M., Lapidot, T., Nussbaum, G., Margalit, R., Cohen, I.R. and Lider, O. (2005) Heat shock protein 60 activates cytokine-associated negative regulator suppressor of cytokine signaling 3 in T cells: effects on signaling, chemotaxis, and inflammation. J Immunol, 175, 276-285. Zhang, Z. and Wang, Y. (2001) [Intracellular signal transduction pathways of IL-1 beta-induced cytotoxicity on primary cultured rat hepatocytes]. Zhonghua Wai Ke Za Zhi, 39, 878-881. Zhorova, E.S., Il''in, L.A., Popov, B.A. and Parfenova, I.M. (2005) [Study of effectiveness of long-term per oral and parenteral cincacine administration at parenteral 241Am incorporation into the organism]. Radiats Biol Radioecol, 45, 207-211. Zugel, U. and Kaufmann, S.H. (1999) Immune response against heat shock proteins in infectious diseases. Immunobiology, 201, 22-35.
熱休克蛋白在很多的細胞中都會穩定表現,在細胞內扮演著很重要的角色。許多研究指出,熱休克蛋白不但參與了自發性的免疫系統,而且對於類鐸受體 (Toll-like receptors,TLRs) 訊號傳遞的路徑也有ㄧ定的影響,造成發炎反應的產生。在先前實驗室的研究發現,在非小細胞肺腺癌中過度表現熱休克蛋白,HLJ1 (Human Liver DnaJ-like protein),會使得介白素八 (interleukin-8,IL-8) 和類鐸受體受到影響,意味著HLJ1可能參與了類鐸受體與介白素的訊號傳遞路徑。因此,想進ㄧ步的探討是否HLJ1會透過類鐸受體的訊號傳遞而調控介白素8的表現。首先,共轉染 (co-transfection) HLJ1及TLR2或是TLR4到細胞中,藉由冷光報導基因分析觀察HLJ1對IL-8的調控。利用TLR2和TLR4及dominant-negative構築,包含:TLR4-mut, TLR2-Δ2, MyD88-DN和TRAF6-DN,進ㄧ步去釐清HLJ1經由哪條TLR路徑去調控IL-8的表現。再利用IL-8啟動子上不同轉錄因子結合區的突變,以冷光報導基因分析,確認HLJ1是經由哪個轉錄因子調控IL-8的表現,結果發現HLJ1主要是由AP1和NF-κB這兩個轉錄因子調控IL-8的表現。暫時性 (transiently) 的共轉染HLJ1和IL-8啟動子上不同突變位置的構築載體,由即時定量反轉錄聚合酶連鎖反應分析在mRNA層次上的變化,發現HLJ1會促進IL-8的表現。在暫時性共轉染HLJ1和TLR2時,更會使得IL-8的表現增加,但共轉染TLR4或TLR2-Δ2時,則沒有類似的情形。另外,在共轉染HLJ1和MyD88-DN或TRAF6-DN的情況下,HLJ1藉由TLR2所誘發的IL-8表現路徑受到阻斷,使HLJ1調控的IL-8表現無法大幅上升。這些結果顯示,HLJ1會經由TLR2-MyD88-TRAF6這條訊息傳遞路徑調控IL-8的表現。此外,從流式細胞技術中可以偵測到細胞表面上人類HLJ1重組蛋白的結合,由即時定量反轉錄聚合酶連鎖反應亦可以發現人類HLJ1重組蛋白會促進IL-8 mRNA的表現。若是先暫時性轉染TLR2後再以人類HLJ1重組蛋白處理細胞,經過冷光報導基因分析後發現IL-8的表現會因為TLR2的轉染,更提升了人類HLJ1重組蛋白對IL-8的調控,但在轉染TLR4或是TLR2-Δ2則沒有類似的情形發生。縱合上述的結果推測不論是人類HLJ1重組蛋白或是內生性的HLJ1主要都會經由TLR2-MyD88-TRAF6-AP1和TLR2-MyD88-TRAF6-NFκB這兩條訊息傳遞路徑來正調控IL-8的表現。

Heat shock proteins (HSPs) expressed constitutively in all cells are essential for several important cellular processes. As reported by several groups, HSPs are not only the potent activators of the innate immune system but also the mediators of the Toll-like receptors (TLRs) signaling pathways leading to proinflammatory responses. In our previous study, overexpression of HLJ1 (Human Liver DnaJ-like protein) in non-small cell lung carcinoma (NSCLC) cells indicated that HLJ1 might involve in the IL-8 regulation and TLRs signal pathways. Therefore, we are interested to know whether HLJ1 involves in the regulation of the TLRs signaling pathway to further regulate IL-8 expression. We first co-transfected HLJ1 with TLR2 or TLR4 constructs to evaluate IL-8 expression by luciferase reporter assay. The mutant and dominant-negative constructs, including TLR4-mut, TLR2-Δ2, MyD88-DN, and TRAF6-DN, were employed to clarify which TLR pathway is involved in IL-8 regulation. Further, the mutant constructs of IL-8 promoter were used to identify which cis-element of IL-8 promoter affected by HLJ1. The results of reporter gene assay further indicated that HLJ1 could regulate IL-8 expression via AP-1 and NFκB transcription factors. We also transiently co-transfected HLJ1 with above constructs to demonstrate IL-8 expression in RNA levels by real-time quantitative RT-PCR. By using real-time quantitative RT-PCR, we demonstrated that HLJ1 could up-regulate IL-8 expression. These results also showed that IL-8 expression was increased when co-transfecting HLJ1 with TLR2 constructs, but not with TLR4 or TLR2-Δ2. In addition, HLJ1 had no effect on regulating IL-8 expression when co-transfecting with MyD88-DN or TRAF6-DN. The results show that HLJ1 up-regulated IL-8 expression via TLR2-MyD88-TRAF6 signal pathway. Otherwise, the extra-recombinant HLJ1 could be observed on the cancer cell surface and up-regulated IL-8 expression by using flow cytometry and IL-8 real-time quantitative RT-PCR. The extra-recombinant HLJ1 could up-regulated IL-8 expression when transiently transfected TLR2 constructs, but not TLR4 or TLR2-Δ2 by using luciferase reporter assay. All of these results suggested that no matter endogenous HLJ1 or recombinant HLJ1 could up-regulate IL-8 expression through TLR2-MyD88-TRAF6-AP1 and TLR2-MyD88-TRAF6-NFκB signal pathways.
其他識別: U0005-2108200616195200
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