A Possible Mechanism of Cisplatin-Induced Tumor Necrosis Factor (TNF)-α Production in Murine Macrophages


Cisplatin has been used for the treatment of various solid cancers or sarcomas; however, it can induce severe adverse effects. Among these adverse effects, nephrotoxicity, which has the potential to be a dose-limiting factor of this agent, develops due to the secretion of tumor necrosis factor-α (TNF-α) from macrophages; however, the precise mechanisms are still unclear. To elucidate possible mechanisms, we investigated the involvement of mitogen-activated protein kinases (MAPK) and reactive oxygen species (ROS) in cisplatin-induced TNF-α mRNA expression and protein production in the mouse macrophage-like cell line, RAW 264. Cisplatin (1 μM) significantly increased TNF-α mRNA expression and protein production. Extracellular-regulated kinase (ERK) and p38 MAPK, but not c-Jun N-terminal kinase (JNK), phosphorylation increased in response to cisplatin. Although an ERK inhibitor (PD98059) suppressed both cisplatin-induced TNF-α mRNA expression and its protein production, a p38 MAPK inhibitor (SB203580) decreased TNF-α protein production only. A JNK inhibitor (SP600125) had no effect on cisplatin-induced TNF-α mRNA expression. Furthermore, a scavenger of ROS, N,N’-dimethylthiourea, suppressed both ERK activation and TNF-α mRNA expression. These results suggest that the phosphorylation of ERK by ROS is involved in cisplatin-induced TNF-α mRNA expression and that the signaling pathway of p38 MAPK is related to TNF-α protein production.

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S. Kim, K. Yamamoto, Y. Nakamura, Y. Otoyo and A. Yamatodani, "A Possible Mechanism of Cisplatin-Induced Tumor Necrosis Factor (TNF)-α Production in Murine Macrophages," Pharmacology & Pharmacy, Vol. 4 No. 2, 2013, pp. 146-151. doi: 10.4236/pp.2013.42021.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Z. Siddik, “Cisplatin: Mode of Cytotoxic Action and Molecular Basis of Resistance,” Oncogene, Vol. 22, 2003, pp. 7265-7279. doi:10.1038/sj.onc.1206933
[2] G. Daugaard and U. Abildgaard, “Cisplatin Nephrotoxicity,” Cancer Chemotherapy and Pharmacology, Vol. 25, No. 1, 1989, pp. 1-9. doi:10.1007/BF00694330
[3] K. P. Kang, D. H. Kim, Y. J. Jun, A. S. Lee, S. Lee, S. Y. Lee, K. Y. Jang, M. J. Sung, S. K. Park and W. Kim, “Alpha-Lipoic Acid Attenuates Cisplatin-Induced Acute Kidney Injury in Mice by Suppressing Renal Inflammation,” Nephrology Dialysis Transplantation, Vol. 24, No. 10, 2009, pp. 3012-3020. doi:10.1093/ndt/gfp242
[4] L. H. Lu, D. J. Oh, Z. Dursun, Z. He, T. S. Hoke, S. Faubel and C. L. Edelstein, “Increased Macrophage Infiltration and Fractalkine Expression in Cisplatin-Induced Acute Renal Failure in Mice,” Journal of Pharmacology and Experimental Therapeutics, Vol. 324, No. 1, 2008, pp. 111-117. doi:10.1124/jpet.107.130161
[5] R. W. Schrier, “Cancer Therapy and Renal Injury,” The Journal of Clinical Investigation, Vol. 110, No. 6, 2002, pp. 743-745. doi:10.1172/JCI16568
[6] G. Ramesh and W. B. Reeves, “p38 MAP Kinase Inhibition Ameliorates Cisplatin Nephrotoxicity in Mice,” American Journal of Physiology Renal Physiology, Vol. 289, No. 8, 2005, pp. 166-174. doi:10.1152/ajprenal.00401.2004
[7] N. A. G. Santos, C. S. C. Bezerra, N. M. Martins, C. Curti, M. L. P. Bianchi and A. C. Santos, “Hydroxyl Radical Scavenger Ameliorates Cisplatin-Induced Nephrotoxicity by Preventing Oxidative Stress, Redox State Unbalance, Impairment of Energetic Metabolism and Apoptosis in Rat Kidney Mitochondria,” Cancer Chemotherapy and Pharmacology, Vol. 61, No. 1, 2008, pp. 145-155. doi:org/10.1007/s00280-007-0459-y
[8] W. Zhang and H. T. Liu, “MAPK Signal Pathway in the Regulation of Cell Proliferation in Mammalian Cells,” Cell Research, Vol. 12, 2002, pp. 9-18. doi:org/10.1038/sj.cr.7290105
[9] K. L. Cowan and K. B. Storey, “Mitogen-Activated Protein Kinases: New Signaling Pathways Functioning in Cellular Responses to Environmental Stress,” The Journal of Experimental Biology, Vol. 206, No. 8, 2003, pp. 1107-1115. doi:org/10.1242/jeb.00220
[10] K. Z. Guyton, M. Gorospe, T. W. Kensler and N. J. Holbrook, “Mitogen-Activated Protein Kinase (MAPK) Activation by Butylated Hydoroxytoluene Hydroperoxide: Implications for Cellular Survival and Tumor Promotion,” Cancer Research, Vol. 56, 1996, pp. 3480-3485.
[11] D. W. Hommes, M. P. Peppelenbosch and S. J. H. Deventer, “Mitogen Activated Protein (MAP) Kinase Signal Transduction Pathways and Novel Anti-Inflammatory targets,” An International Journal of Gastroenterology and Hepatology, Vol. 29, No. 1, 2003, pp. 144-151. doi:org/10.1136/gut.52.1.144
[12] G. Ramesh, S. R. Kimball, L. S. Jefferson and W. B. Reeves, “Endotoxin and Cisplatin Synergistically Stimulate TNF-α Production by Renal Epithelial Cells,” American Journal of Physiology, Vol. 292, No. 2, 2007, pp. 812-819. doi:org/10.1152/ajprenal.00277.2006
[13] B. Zhang, G. Ramesh, S. Uematsu, S. Akira and W. B. Reeves, “TLR4 Signaling Mediates Inflammation and Tissue Injury in Nephrotoxicity,” Journal of the American Society of Nephrology, Vol. 19, No. 5, 2008, pp. 923-932. doi:10.1681/ASN.2007090982
[14] T. Suzuki, I. Hide, K. Ido, S. kohsaka, K. Inoue and Y. Nakata, “Production and Release of Neuroprotective Tumor Necrosis Factor by P2X7 Receptor-Activated Microglia,” The Journal of Neuroscience, Vol. 24, No. 1, 2004, pp. 1-7. doi:10.1523/JNEUROSCI.3792-03.2004
[15] J. L. Swantek, M. H. Cobb and T. D. Geppert, “Jun N-Terminal Kinase/Stress-Activated Protein Kinase (JNK/ SAPK) Is Required for Lipopolysaccharide Stimulation of Tumor Necrosis Factor Alpha (TNF-α) Translation: Glucocorticoids Inhibit TNF-α Translation by Blocking JNK/SAPK,” Molecular and Cellular Biology, Vol. 17, 1997, pp. 6274-6282.
[16] I. Sánchez-Pérez and R. Perona, “Lack of c-Jun Activity Increases Survival to Cisplatin,” FEBS Letters, Vol. 453, No. 1-2, 1999, pp. 151-158. doi:10.1016/S0014-5793(99)00690-0
[17] I. Sánchez-Pérez, S. A. Benitah, M. Martínez-Gomariz, J. C. Lacal and R. Perona, “Cell Stress and MEKK1-Mediated c-Jun Activation Modulate NFκB Activity and Cell Viability,” Molecular Biology of the Cell, Vol. 13, No. 8, 2002, pp. 2933-2945. doi:10.1091/mbc.E02-01-0022
[18] K. M. Rao, “MAP Kinase Activation in Macrophages,” Journal of Leukocyte Biology, Vol. 69, No. 1, 2001, pp. 3-10.
[19] Y. Geng, E. Gulbins, A. Altman and M. Lotz, “Monocyte Deactivation by Interleukin 10 via Inhibition of Tyrosine Kinase Activity and the Ras Signaling Pathway,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 91, No. 18, 1994, pp. 8602-8606. doi:10.1073/pnas.91.18.8602
[20] T. Reimann, D. B?scher, R. A. Hipskind, S. Krautwald, M. Lohmann-Matthes and M. Baccarini, “Lipopolysaccharide Induces Activation of the Raf-1/MAP Kinase Pathway,” The American Association of Immunologists, Vol. 153, 1994, pp. 5740-5749.
[21] M. S. Lee, Y. J. Kim, “Signaling Pathways Downstream of Pattern-Recognition Receptors and Their Cross Talk,” Annual Review of Biochemistry, Vol. 76, 2007, pp. 447-480. doi:10.1146/annurev.biochem.76.060605.122847
[22] M. J. Smolinska, T. H. Page, A. M. Urbaniak, B. E. Mutch and N. J. Horwood, “Hck Tyrosine Kinase Regulates TLR4-Induced TNF and IL-6 Production via AP-1,” The Journal of Immunology, Vol. 187, No. 11, 2011, pp. 6043-6051. doi:10.4049/jimmunol.1100967
[23] A. B. Carter, M. M. Monick and G. W. Hunninghake, “Both Erk and p38 Kinases Are Necessary for Cytokine Gene Transcription,” American Journal of Respiratory Cell and Molecular Biology, Vol. 20, No. 4, 1999, pp. 751-758. doi:10.1165/ajrcmb.20.4.3420
[24] J. A. Frost, T. D. Geppert, M. H. Cobb and J. R. Feramisco, “A Requirement for Extracellular Signal-Regulated Kinase (ERK) Function in the Activation of AP-1 by Ha-Ras, Phorbol 12-Myristate 13-Acetate, and Serum,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 91, No. 9, 1994, pp. 3844-3848. doi:10.1073/pnas.91.9.3844
[25] S. Shishodia, A. Sodhi and A. Shrivastava, “Involvement of RAS and MAP Kinase (ERK-1) in Cisplatin-Induced Activation of Murine Bone Marrow-Derived Macrophages,” Biochemistry and Molecular Biology International, Vol. 45, 1998, pp. 527-534.
[26] J. Dong, S. Ramachandiran, K. Tikoo, Z. Jia, S. S. Lau and T. J. Monks, “EGFR-Independent Activation of p38 MAPK and EGFR-Dependent Activation of ERK1/2 Are Required for ROS-Induced Renal Cell Death,” American Journal of Physiology Renal Physiology, Vol. 287, No. 5, 2004, pp. 1049-1058. doi:10.1152/ajprenal.00132.2004
[27] A. Sabri and P. A. Lucchesi, “ANG II and Cardiac Myocyte Contractility: p38 Is Not Stressed Out!” American Journal of Physiology Heart and circulatory Physiology, Vol. 290, No. 1, 2006, pp. 72-73. doi:10.1152/ajpheart.00873.2005
[28] E. M. Galan-Moya, M. A. Cruz-Morcillo, M. L. Valero, J. L. Callejas-Valera, P. Melgar-Rojas, J. H. Losa, M. Salcedo, A. Fernández-Aramburo, S. R. Cajai and R. Sánchezprieto, “Balance between MKK6 and MKK3 Mediates p38 MAPK Associated Resistance to Cisplatin in NDCLC,” PLOS ONE, Vol. 6, No. 12, 2011, pp. 1-11. doi:10.1371/journal.pone.0028406
[29] X. Yao, K. Panichpisal, N. Kurtzman and K. Nugent, “Cisplatin Nephrotoxicity: A Review,” The American Journal of the Medical Sciences, Vol. 334, No. 2, 2007, pp. 115-124. doi:10.1097/MAJ.0b013e31812dfe1e
[30] C. Runchel, A. Matsuzawa and H. Ichijo, “Mitogen-Activated Protein Kinases in Mammalian Oxidative Stress Responses,” Antioxidants and Redox Signaling, Vol. 15, No. 1, 2011, pp. 205-218. doi:10.1089/ars.2010.3733
[31] R. B. Fox, “Prevention of Granulocyte-Mediated Oxidant Lung Injury in Rats by a Hydroxyl Radical Scavenger, Dimethylthiourea,” The Journal of Clinical Investigation, Vol. 74, No. 4, 1984, pp. 1456-1464. doi:10.1172/JCI111558
[32] B. Geering, U. Gurzeler, E. Federzoni, T. Kaufmann and H. U. Simon, “A Novel TNFR1-Triggered Apoptosis Pathway Mediated by Class IA PI3Ks in Neutrophils,” Blood, Vol. 117, 2011, pp. 5953-5962. doi:10.1182/blood-2010-11-322206
[33] J. Dong, S. Ramachandiran, K. Tikoo, Z. Jia, S. S. Lau and T. J. Monks, “EGFR-Independent Activation of p38 MAPK and EGFR-Dependent Activation of ERK1/2 Are Required for ROS-Induced Renal Cell Death,” American Journal of Physiology Renal Physiology, Vol. 29, 2004, pp. 1049-1058.
[34] W. Hove, L. A. Houben, J. A. M. Raaijmakers, M. Bracke and L. Koenderman, “Differential Regulation of TNFα and GM-CSF Induced Activation of P38 MAPK in Neutrophils and Eosinophils,” Molecular Immunology, Vol. 44, No. 9, 2007, pp. 2492-2496. doi:10.1016/j.molimm.2006.10.009
[35] K. Suzuki, M. Hino, F. Hato, N. Tatsumi and S. Kitagawa, “Cytokine-Specific Activation of Distinct Mitogen-Activated Protein Kinase Subtype Cascades in Human Neutrophils Stimulated by Granulocyte Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor, and Tumor Necrosis Factor-α,” Blood, Vol. 93, 1999, pp. 341-349.

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