Oral PTCTS (Particulated Transialidase) Removes Serum Microparticles and Decreases Inflammation in Atherosclerotic Plaques of Rabbits
Author(s)
Shérrira M. Garavelo1,
Jaqueline J. Pereira1,
Nilsa S. Y. Wadt1,
Marcia M. Reis1,
Renata N. Ikegami1,
Joyce T. Kawakami1,
Abdelali Agouni2,3,
Suely A. P. Palomino1,
Dulcinéia Abdalla4,
Maria de Lourdes Higuchi1
Affiliation(s)
1 Heart Institute (InCor), University of Sao Paulo Clinics Hospital, Sao Paulo, Brazil. 2 Faculty of Health and Medical Sciences (FHMS), University of Surrey, Guildford, UK. 3 College of Pharmacy, Qatar University, Doha, Qatar. 4 Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
1 Heart Institute (InCor), University of Sao Paulo Clinics Hospital, Sao Paulo, Brazil. 2 Faculty of Health and Medical Sciences (FHMS), University of Surrey, Guildford, UK. 3 College of Pharmacy, Qatar University, Doha, Qatar. 4 Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
ABSTRACT
Background: Previous studies showed that atherosclerotic plaque vulnerability was related with microparticles (MPs)-vesicles larger than 100 nm, which released MMP9 collagenase. In our previous study, intramuscular injection of a new drug (PTCTS) normalized oxidized LDL serum levels and reduced rabbit atherosclerosis. Now, we studied administration of oral PTCTS in order to clarify anti-atherosclerotic mechanism of action, analyzing if the treatment removed MPs containing ox-LDL and Mycoplasma pneumoniae antigens and improved the immune response. Methods: We compared two groups of rabbits. Control group (CG, n = 6)—1% cholesterol enriched diet for 12 weeks; Treated group (TG, n = 8)—1% cholesterol enriched diet for 12 weeks with administration of PTCTS (400 μl/day) during the last 6 weeks of diet. The animals had their blood collected, in three different phases of the protocol before being fed with hypercholesterolemic diet, before being treated with water or PTCTS and at the moment of sacrifice. The serum was submitted to immunofluorescence technique to evaluate the quantity of microparticles marked with antibodies against Mycoplasma pneumoniae and ox-LDL. A fragment of aorta was submitted to immunohistochemical detection of antigens from MMP9, ox-LDL, NF-κB and IL-1β. Results: PTCTS showed significant reduction in MMP-9 (P = 0.001) and a tendency of reducing IL-1β (P = 0.09) in the aortic plaques compared with CG. In the serum, PTCTS was able to remove microparticles containing antigen of ox-LDL (P = 0.004) and Mycoplasma pneumoniae (P < 0.001). Conclusion: Oral treatment with PTCTS presented more adequate inflammatory response by reducing levels of ox-LDL, IL-1β and mycoplasma, as well as a better stabilization of the atheromatous plaque by reducing levels of MMP-9, avoiding plaque rupture, without causing mortality or toxicity.
Background: Previous studies showed that atherosclerotic plaque vulnerability was related with microparticles (MPs)-vesicles larger than 100 nm, which released MMP9 collagenase. In our previous study, intramuscular injection of a new drug (PTCTS) normalized oxidized LDL serum levels and reduced rabbit atherosclerosis. Now, we studied administration of oral PTCTS in order to clarify anti-atherosclerotic mechanism of action, analyzing if the treatment removed MPs containing ox-LDL and Mycoplasma pneumoniae antigens and improved the immune response. Methods: We compared two groups of rabbits. Control group (CG, n = 6)—1% cholesterol enriched diet for 12 weeks; Treated group (TG, n = 8)—1% cholesterol enriched diet for 12 weeks with administration of PTCTS (400 μl/day) during the last 6 weeks of diet. The animals had their blood collected, in three different phases of the protocol before being fed with hypercholesterolemic diet, before being treated with water or PTCTS and at the moment of sacrifice. The serum was submitted to immunofluorescence technique to evaluate the quantity of microparticles marked with antibodies against Mycoplasma pneumoniae and ox-LDL. A fragment of aorta was submitted to immunohistochemical detection of antigens from MMP9, ox-LDL, NF-κB and IL-1β. Results: PTCTS showed significant reduction in MMP-9 (P = 0.001) and a tendency of reducing IL-1β (P = 0.09) in the aortic plaques compared with CG. In the serum, PTCTS was able to remove microparticles containing antigen of ox-LDL (P = 0.004) and Mycoplasma pneumoniae (P < 0.001). Conclusion: Oral treatment with PTCTS presented more adequate inflammatory response by reducing levels of ox-LDL, IL-1β and mycoplasma, as well as a better stabilization of the atheromatous plaque by reducing levels of MMP-9, avoiding plaque rupture, without causing mortality or toxicity.
Cite this paper
Garavelo, S. , Pereira, J. , Wadt, N. , Reis, M. , Ikegami, R. , Kawakami, J. , Agouni, A. , Palomino, S. , Abdalla, D. and Higuchi, M. (2015) Oral PTCTS (Particulated Transialidase) Removes Serum Microparticles and Decreases Inflammation in Atherosclerotic Plaques of Rabbits. Advances in Nanoparticles, 4, 107-115. doi: 10.4236/anp.2015.44012.
Garavelo, S. , Pereira, J. , Wadt, N. , Reis, M. , Ikegami, R. , Kawakami, J. , Agouni, A. , Palomino, S. , Abdalla, D. and Higuchi, M. (2015) Oral PTCTS (Particulated Transialidase) Removes Serum Microparticles and Decreases Inflammation in Atherosclerotic Plaques of Rabbits. Advances in Nanoparticles, 4, 107-115. doi: 10.4236/anp.2015.44012.
References
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http://dx.doi.org/10.1016/s0002-8703(99)70266-8 [2] Libby, P. (2002) Inflammation in Atherosclerosis. Nature, 420, 868-874.
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http://dx.doi.org/10.1038/35025203 [4] Cybulsky, M.I., Iiyama, K., Li, H., Zhu, S., Chen, M., Iiyama, M., Davis, V., Gutierrez-Ramos, J.C., Connelly, P.W. and Milstone, D.S. (2001) A Major Role for VCAM-1, but Not ICAM-1, in Early Atherosclerosis. Journal of Clinical Investigation, 107, 1255-1262.
http://dx.doi.org/10.1172/JCI11871 [5] Binder, C.J., Hartvigsen, K., Chang, M.K., Miller, M., Broid, D., Palinski, W., Curtiss, L.K., Corr, M. and Witztum, J.L. (2004) IL-5 Links Adaptative and Natural Immunity Specific for Epitopes of Oxidized LDL and Protects from Atherosclerosis. Journal of Clinical Investigation, 114, 427-437.
http://dx.doi.org/10.1172/JCI200420479 [6] Brand, K., Eisele, T., Kreusel, U., Page, M., Page, S., Haas, M., Gerling, A., Kaltschmidt, C., Neumann, F.J., Mackman, N., Baeurele, P.A., Walli, A.K. and Neumeier, D. (1997) Dysregulation of Monocytic Nuclear Factor-κB by Oxidized Low-Density Lipoprotein. Arteriosclerosis, Thrombosis, and Vascular Biology, 17, 1901-1909.
http://dx.doi.org/10.1161/01.ATV.17.10.1901 [7] Muller, J.R. and Siebenlist, U. (2003) Lymphotoxinbeta Receptor Induces Sequential Activation of Distinct NF-κB Factors via Separate Signaling Pathways. The Journal of Biological Chemistry, 278, 12006-12012.
http://dx.doi.org/10.1074/jbc.M210768200 [8] Collins, T. and Cybulsky, M.I. (2001) NF-κB: Pivotal Mediator or Innocent Bystander in Atherogenesis? Journal of Clinical Investigation, 107, 255-264.
http://dx.doi.org/10.1172/JCI10373 [9] Berliner, J.A., Territo, M.C., Sevanian, A., Ramin, S., Kim, J.A., Bamshad, B., Esterson, M. and Fogelman, A.M. (1990) Minimally Modified Low-Density Lipoprotein Stimulates Monocyte Endothelial Interactions. Journal of Clinical Investigation, 85, 1260-1266.
http://dx.doi.org/10.1172/JCI114562 [10] Dechend, R., Maass, M., Gieffers, J., Dietz, R., Scheidereit, C., Leutz, A. and Gulba, D.C. (1999) Chlamydia Pneumoniae Infection of Vascular Smooth Muscle and Endothelial Cells Activates NF-κB and Induces Tissue Factor and PAI- 1 Expression: A Potential Link to Accelerated Arteriosclerosis. Circulation, 100, 1369-1373.
http://dx.doi.org/10.1161/01.CIR.100.13.1369 [11] Maia, I.L., Nicolau, J.C., Machado, M.N., et al. (2005) Prevalência de Chlamydia pneumoniaee Mycoplasma pneu- moniae em diferentes formas de doença coronariana. Arquivos Brasileiros de Cardiologia, 92, 439-445. [12] Winther, M.P.J., Kanters, E., Kraal, G. and Hofker, M.H. (2005) Nuclear Factor κB Signaling in Atherogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 904-914.
http://dx.doi.org/10.1161/01.ATV.0000160340.72641.87 [13] Brach, M.A., Henschler, R., Mertelsmann, R.H. and Herrmann, F. (1991) Regulation of M-CSF Expression by M-CSF: Role of Protein Kinase C and Transcription Factor NF-κB. Pathobiology, 59, 284-288.
http://dx.doi.org/10.1159/000163664 [14] Bond, M., Fabunmi, R.P., Baker, A.H. and Newby, A.C. (1998) Synergistic Upregulation of Metalloproteinase-9 by Growth Factors and Inflammatory Cytokines: An Absolute Requirement for Transcription Factor NF-κB. FEBS Letters, 435, 29-34.
http://dx.doi.org/10.1016/S0014-5793(98)01034-5 [15] Galis, Z.S., Johnson, C., Godin, D., Magid, R., Shipley, J.M., Senior, R.M. and Ivan, E. (2002) Targeted Disruption of the Matrix Metalloproteinase-9 Gene Impairs Smooth Muscle Cell Migration and Geometrical Arterial Remodeling. Circulation Research, 91, 852-859.
http://dx.doi.org/10.1161/01.RES.0000041036.86977.14 [16] Shah, K.P. and Galis, Z.S. (2001) Matrix Metalloproteinase Hypothesis of Plaque Rupture Players Keep Piling up but Questions Remain. Circulation, 104, 1878-1880. [17] Packard, R.R.S. and Libby, P. (2008) Inflammation in Atherosclerosis: From Vascular Biology to Biomarker Discovery and Risk Prediction. Clinical Chemistry, 54, 24-38.
http://dx.doi.org/10.1373/clinchem.2007.097360 [18] Roggerio, A., Sambiase, N.V., Palomino, S.A.P., Castro, M.A.P., Silva, E.S., Stolf, N.G. and Higuchi, M.L. (2013) Correlation of Bacterial Coinfection versus Matrix Metalloproteinase 9 and Tissue Inhibitor of Metalloproteinase 1 Expression in Aortic Aneurysm and Atherosclerosis. Annals of Vascular Surgery, 27, 964-971.
http://dx.doi.org/10.1016/j.avsg.2013.02.012 [19] Higuchi, M.L., Reis, M.M., Sambiase, N.V., Palomino, S.A.P., Castelli, J.B., Gutierrez, O.S., Aiello, V.D. and Ramires, J.A.F. (2003) Co-infecção por Mycoplasma pneumoniae e Chlamydia pneumoniae em Placas Rotas associadas a Infarto Agudo do Miocárdio. Arquivos Brasileiros de Cardiologia, 81, 1-11. [20] Assis, R.M., Higuchi, M.L., Reis, M.M., Palomino, S.A.P., Hirata, R.D.C. and Hirata, M.H. (2014) Involvement of TLR2 and TLR4, Chlamydophila pneumoniae and Mycoplasma pneumoniae in Adventitial Inflammation of Aortic Atherosclerotic Aneurysm. World Journal of Cardiovascular Diseases, 4, 14-22.
http://dx.doi.org/10.4236/wjcd.2014.41004 [21] Ikegami, R.N., Kawakami, J.T., Abdalla, D.S.P., Santos, R.D., Filho, R.K., Ramires, J.A.F. and Higuchi, M.L. (2015) Infection and Microparticles May Cause Complication of Atherosclerotic Plaques. Journal of Diabetes & Metabolism, 6, 1-4.
http://dx.doi.org/10.4172/2155-6156.1000537 [22] Higuchi, M.L., Santos, M.H.H., Fagundes, R.Q., Palomino, S.A.P. and Reis, M.M. (2011) Trans-Sialidase from Trypanosoma cruzi: Na Anti-Atherosclerotic Drug. Proceedings of the Keystone Symposia on Molecular and Cellular Biology—Drugs from Bugs: The Anti-Inflammatory Drugs of Tomorrow, Snowbird Resort, 3-7 April 2011, 66. [23] Santos, M.H.H., Ikegami, R.N., Reis, M.M., Fagundes, R.Q. and Higuchi, M.L. (2007) A New Therapeutic Proposal for Lipid Lowering Treatment: Association of Transialidase and Anti-Oxidant Elements. Na Experimental Study in Rabbits. Proceedings of the XVI International Symposium on Drugs Affecting Lipid Metabolism—DALM, New York, 4-7 October 2007, 474. [24] Greenberg, S. and Grinstein, S. (2002) Phagocytosis and Innate Immunity. Current Opinion in Immunology, 14, 136- 145.
http://dx.doi.org/10.1016/S0952-7915(01)00309-0 [25] Hansson, G.K., Libby, P., Schonbeck, U. and Yan, Z.Q. (2002) Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis. Circulation Research, 91, 281-291.
http://dx.doi.org/10.1161/01.RES.0000029784.15893.10 [26] Iyama, K., Zhang, S. and Lo, S.C. (2001) Effects of Mycoplasmal LAMPs on Receptor Responses to Steroid Hormones in Mammalian Cells. Current Microbiology, 43, 163-169.
http://dx.doi.org/10.1007/s002840010281 [27] Wise, K.S., Kim, M.F., Theiss, P.M. and Lo, S.C. (1993) A Family of Strain-Variant Surface Lipoproteins of Mycoplasma fermentans. Infection and Immunity, 61, 3327-3333. [28] Pucci, B., Kasten, M. and Giordano, A. (2000) Cell Cycle and Apoptosis. Neoplasia, 2, 291-299.
http://dx.doi.org/10.1038/sj.neo.7900101 [29] Muneta, Y., Uenishi, H., Kikuma, R., Yoshihara, K., Shimoji, Y., Yamamoto, R., Hamashina, N., Yokomizo, Y. and Mori, Y. (2003) Porcine TLR2 and TLR6: Identification and Their Involvement in Mycoplasma hyopneumoniae Infection. Journal of Interferon & Cytokine Research, 23, 583-590.
http://dx.doi.org/10.1089/107999003322485080 [30] You, X., Yimou, W., Zeng, Y., Deng, Z., Qiu, H. and Minjun, Y. (2008) Mycoplasma genitalium-Derived Lipid- Associated Membrane Proteins Induce Activation of MAPKs, NF-kB and AP-1 in THP-1 Cells. FEMS Immunology & Medical Microbiology, 52, 228-236.
http://dx.doi.org/10.1111/j.1574-695X.2007.00366.x [31] May, M.J. and Ghosh, S. (1998) Signal Transduction through NF-κB. Immunology Today, 19, 80-88.
http://dx.doi.org/10.1016/S0167-5699(97)01197-3 [32] Siebenlist, U., Franzoso, G. and Brown, K. (1994) Structure, Regulation and Function of NF-κB. Annual Review of Cell Biology, 10, 405-455.
http://dx.doi.org/10.1146/annurev.cb.10.110194.002201
[1] Ross, R. (1999) Atherosclerosis Is an Inflammatory Disease. American Heart Journal 138, S419-S420.
http://dx.doi.org/10.1016/s0002-8703(99)70266-8 [2] Libby, P. (2002) Inflammation in Atherosclerosis. Nature, 420, 868-874.
http://dx.doi.org/10.1038/nature01323 [3] Lusis, A.J. (2000) Atherosclerosis. Nature, 407, 233-241.
http://dx.doi.org/10.1038/35025203 [4] Cybulsky, M.I., Iiyama, K., Li, H., Zhu, S., Chen, M., Iiyama, M., Davis, V., Gutierrez-Ramos, J.C., Connelly, P.W. and Milstone, D.S. (2001) A Major Role for VCAM-1, but Not ICAM-1, in Early Atherosclerosis. Journal of Clinical Investigation, 107, 1255-1262.
http://dx.doi.org/10.1172/JCI11871 [5] Binder, C.J., Hartvigsen, K., Chang, M.K., Miller, M., Broid, D., Palinski, W., Curtiss, L.K., Corr, M. and Witztum, J.L. (2004) IL-5 Links Adaptative and Natural Immunity Specific for Epitopes of Oxidized LDL and Protects from Atherosclerosis. Journal of Clinical Investigation, 114, 427-437.
http://dx.doi.org/10.1172/JCI200420479 [6] Brand, K., Eisele, T., Kreusel, U., Page, M., Page, S., Haas, M., Gerling, A., Kaltschmidt, C., Neumann, F.J., Mackman, N., Baeurele, P.A., Walli, A.K. and Neumeier, D. (1997) Dysregulation of Monocytic Nuclear Factor-κB by Oxidized Low-Density Lipoprotein. Arteriosclerosis, Thrombosis, and Vascular Biology, 17, 1901-1909.
http://dx.doi.org/10.1161/01.ATV.17.10.1901 [7] Muller, J.R. and Siebenlist, U. (2003) Lymphotoxinbeta Receptor Induces Sequential Activation of Distinct NF-κB Factors via Separate Signaling Pathways. The Journal of Biological Chemistry, 278, 12006-12012.
http://dx.doi.org/10.1074/jbc.M210768200 [8] Collins, T. and Cybulsky, M.I. (2001) NF-κB: Pivotal Mediator or Innocent Bystander in Atherogenesis? Journal of Clinical Investigation, 107, 255-264.
http://dx.doi.org/10.1172/JCI10373 [9] Berliner, J.A., Territo, M.C., Sevanian, A., Ramin, S., Kim, J.A., Bamshad, B., Esterson, M. and Fogelman, A.M. (1990) Minimally Modified Low-Density Lipoprotein Stimulates Monocyte Endothelial Interactions. Journal of Clinical Investigation, 85, 1260-1266.
http://dx.doi.org/10.1172/JCI114562 [10] Dechend, R., Maass, M., Gieffers, J., Dietz, R., Scheidereit, C., Leutz, A. and Gulba, D.C. (1999) Chlamydia Pneumoniae Infection of Vascular Smooth Muscle and Endothelial Cells Activates NF-κB and Induces Tissue Factor and PAI- 1 Expression: A Potential Link to Accelerated Arteriosclerosis. Circulation, 100, 1369-1373.
http://dx.doi.org/10.1161/01.CIR.100.13.1369 [11] Maia, I.L., Nicolau, J.C., Machado, M.N., et al. (2005) Prevalência de Chlamydia pneumoniaee Mycoplasma pneu- moniae em diferentes formas de doença coronariana. Arquivos Brasileiros de Cardiologia, 92, 439-445. [12] Winther, M.P.J., Kanters, E., Kraal, G. and Hofker, M.H. (2005) Nuclear Factor κB Signaling in Atherogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 904-914.
http://dx.doi.org/10.1161/01.ATV.0000160340.72641.87 [13] Brach, M.A., Henschler, R., Mertelsmann, R.H. and Herrmann, F. (1991) Regulation of M-CSF Expression by M-CSF: Role of Protein Kinase C and Transcription Factor NF-κB. Pathobiology, 59, 284-288.
http://dx.doi.org/10.1159/000163664 [14] Bond, M., Fabunmi, R.P., Baker, A.H. and Newby, A.C. (1998) Synergistic Upregulation of Metalloproteinase-9 by Growth Factors and Inflammatory Cytokines: An Absolute Requirement for Transcription Factor NF-κB. FEBS Letters, 435, 29-34.
http://dx.doi.org/10.1016/S0014-5793(98)01034-5 [15] Galis, Z.S., Johnson, C., Godin, D., Magid, R., Shipley, J.M., Senior, R.M. and Ivan, E. (2002) Targeted Disruption of the Matrix Metalloproteinase-9 Gene Impairs Smooth Muscle Cell Migration and Geometrical Arterial Remodeling. Circulation Research, 91, 852-859.
http://dx.doi.org/10.1161/01.RES.0000041036.86977.14 [16] Shah, K.P. and Galis, Z.S. (2001) Matrix Metalloproteinase Hypothesis of Plaque Rupture Players Keep Piling up but Questions Remain. Circulation, 104, 1878-1880. [17] Packard, R.R.S. and Libby, P. (2008) Inflammation in Atherosclerosis: From Vascular Biology to Biomarker Discovery and Risk Prediction. Clinical Chemistry, 54, 24-38.
http://dx.doi.org/10.1373/clinchem.2007.097360 [18] Roggerio, A., Sambiase, N.V., Palomino, S.A.P., Castro, M.A.P., Silva, E.S., Stolf, N.G. and Higuchi, M.L. (2013) Correlation of Bacterial Coinfection versus Matrix Metalloproteinase 9 and Tissue Inhibitor of Metalloproteinase 1 Expression in Aortic Aneurysm and Atherosclerosis. Annals of Vascular Surgery, 27, 964-971.
http://dx.doi.org/10.1016/j.avsg.2013.02.012 [19] Higuchi, M.L., Reis, M.M., Sambiase, N.V., Palomino, S.A.P., Castelli, J.B., Gutierrez, O.S., Aiello, V.D. and Ramires, J.A.F. (2003) Co-infecção por Mycoplasma pneumoniae e Chlamydia pneumoniae em Placas Rotas associadas a Infarto Agudo do Miocárdio. Arquivos Brasileiros de Cardiologia, 81, 1-11. [20] Assis, R.M., Higuchi, M.L., Reis, M.M., Palomino, S.A.P., Hirata, R.D.C. and Hirata, M.H. (2014) Involvement of TLR2 and TLR4, Chlamydophila pneumoniae and Mycoplasma pneumoniae in Adventitial Inflammation of Aortic Atherosclerotic Aneurysm. World Journal of Cardiovascular Diseases, 4, 14-22.
http://dx.doi.org/10.4236/wjcd.2014.41004 [21] Ikegami, R.N., Kawakami, J.T., Abdalla, D.S.P., Santos, R.D., Filho, R.K., Ramires, J.A.F. and Higuchi, M.L. (2015) Infection and Microparticles May Cause Complication of Atherosclerotic Plaques. Journal of Diabetes & Metabolism, 6, 1-4.
http://dx.doi.org/10.4172/2155-6156.1000537 [22] Higuchi, M.L., Santos, M.H.H., Fagundes, R.Q., Palomino, S.A.P. and Reis, M.M. (2011) Trans-Sialidase from Trypanosoma cruzi: Na Anti-Atherosclerotic Drug. Proceedings of the Keystone Symposia on Molecular and Cellular Biology—Drugs from Bugs: The Anti-Inflammatory Drugs of Tomorrow, Snowbird Resort, 3-7 April 2011, 66. [23] Santos, M.H.H., Ikegami, R.N., Reis, M.M., Fagundes, R.Q. and Higuchi, M.L. (2007) A New Therapeutic Proposal for Lipid Lowering Treatment: Association of Transialidase and Anti-Oxidant Elements. Na Experimental Study in Rabbits. Proceedings of the XVI International Symposium on Drugs Affecting Lipid Metabolism—DALM, New York, 4-7 October 2007, 474. [24] Greenberg, S. and Grinstein, S. (2002) Phagocytosis and Innate Immunity. Current Opinion in Immunology, 14, 136- 145.
http://dx.doi.org/10.1016/S0952-7915(01)00309-0 [25] Hansson, G.K., Libby, P., Schonbeck, U. and Yan, Z.Q. (2002) Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis. Circulation Research, 91, 281-291.
http://dx.doi.org/10.1161/01.RES.0000029784.15893.10 [26] Iyama, K., Zhang, S. and Lo, S.C. (2001) Effects of Mycoplasmal LAMPs on Receptor Responses to Steroid Hormones in Mammalian Cells. Current Microbiology, 43, 163-169.
http://dx.doi.org/10.1007/s002840010281 [27] Wise, K.S., Kim, M.F., Theiss, P.M. and Lo, S.C. (1993) A Family of Strain-Variant Surface Lipoproteins of Mycoplasma fermentans. Infection and Immunity, 61, 3327-3333. [28] Pucci, B., Kasten, M. and Giordano, A. (2000) Cell Cycle and Apoptosis. Neoplasia, 2, 291-299.
http://dx.doi.org/10.1038/sj.neo.7900101 [29] Muneta, Y., Uenishi, H., Kikuma, R., Yoshihara, K., Shimoji, Y., Yamamoto, R., Hamashina, N., Yokomizo, Y. and Mori, Y. (2003) Porcine TLR2 and TLR6: Identification and Their Involvement in Mycoplasma hyopneumoniae Infection. Journal of Interferon & Cytokine Research, 23, 583-590.
http://dx.doi.org/10.1089/107999003322485080 [30] You, X., Yimou, W., Zeng, Y., Deng, Z., Qiu, H. and Minjun, Y. (2008) Mycoplasma genitalium-Derived Lipid- Associated Membrane Proteins Induce Activation of MAPKs, NF-kB and AP-1 in THP-1 Cells. FEMS Immunology & Medical Microbiology, 52, 228-236.
http://dx.doi.org/10.1111/j.1574-695X.2007.00366.x [31] May, M.J. and Ghosh, S. (1998) Signal Transduction through NF-κB. Immunology Today, 19, 80-88.
http://dx.doi.org/10.1016/S0167-5699(97)01197-3 [32] Siebenlist, U., Franzoso, G. and Brown, K. (1994) Structure, Regulation and Function of NF-κB. Annual Review of Cell Biology, 10, 405-455.
http://dx.doi.org/10.1146/annurev.cb.10.110194.002201