The Signaling Pathways in Nitric Oxide Production by Neutrophils Exposed to N-nitrosodimethylamine

Author(s): Wioletta Ratajczak-Wrona*, Ewa Jablonska

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 2 , 2019

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Graphical Abstract:


Background: Polymorphonuclear neutrophils (PMNs) play a crucial role in the innate immune system’s response to microbial pathogens through the release of reactive nitrogen species, including Nitric Oxide (NO).

Methods: In neutrophils, NO is produced by the inducible Nitric Oxide Synthase (iNOS), which is regulated by various signaling pathways and transcription factors. N-nitrosodimethylamine (NDMA), a potential human carcinogen, affects immune cells. NDMA plays a major part in the growing incidence of cancers. Thanks to the increasing knowledge on the toxicological role of NDMA, the environmental factors that condition the exposure to this compound, especially its precursors- nitrates arouse wide concern.

Results: In this article, we present a detailed summary of the molecular mechanisms of NDMA’s effect on the iNOS-dependent NO production in human neutrophils.

Conclusion: This research contributes to a more complete understanding of the mechanisms that explain the changes that occur during nonspecific cellular responses to NDMA toxicity.

Keywords: N-nitrosodimethylamine (NDMA), neutrophils, Nitric Oxide (NO), inducible Nitric Oxide Synthase (iNOS), MAPK PI3K–Akt/PKB, JAK/STAT, AP1, NF-kB.

Jablonski, J. N-nitrosodimethylamine - toxicologic significance. Post Hig. Med. Dosw., 2001, 55, 317-337.
Lijinsky, W. Chemistry and biology of N-nitroso compounds; Cambridge University Press: Cambridge , 1992.
Tricker, A.R.; Preussmann, R. Carcinogenic N-nitrosamines in the diet: Occurrence, formation, mechanisms, and carcinogenic potential. Mutat. Res., 1991, 259, 277-289.
Zeilmaker, M.J.; Bakker, M.I.; Schothorst, R.; Slob, W. Risk assessment of N-nitrosodimethylamine formed endogenously after fish-with-vegetable meals. Toxicol. Sci., 2010, 116, 323-335.
Vermeer, I.T.; Engels, L.G.; Pachen, D.M.; Dallinga, J.W.; Kleinjans, J.C.; van Maanen, J.M. Intragastric volatile N-nitrosamines, nitrite, pH, and Helicobacter pylori during long-term treatment with omeprazole. Gastroenterology, 2001, 121, 517-525.
Vermeer, I.T.; Pachen, D.M.; Dallinga, J.W.; Kleinjans, J.C.; van Maanen, J.M. Volatile N-nitrosamine formation after intake of nitrate at the ADI level in combination with an amine-rich diet. Environ. Health Perspect., 1998, 106, 459-463.
Graves, R.J.; Swann, P.F. Clearance of N-nitrosodimethylamine and N-nitrosodiethylamine by the perfused rat liver. Relationship to the Km and Vmax for nitrosamine metabolism. Biochem. Pharmacol., 1993, 45, 983-989.
Beyrau, M.; Bodkin, J.V.; Nourshargh, S. Neutrophil heterogeneity in health and disease: A revitalized avenue in inflammation and immunity. Open Biol., 2012, 2, 120-134.
Silvestre-Roig, C.; Hidalgo, A.; Soehnlein, O. Neutrophil heterogeneity: Implications for homeostasis and pathogenesis. Blood, 2016, 5, 2173-2181.
Lirk, P.; Hoffmann, G.; Rieder, J. Inducible nitric oxide synthase; Time for reap-praisal. Curr. Drug Targets, 2002, 1, 89-108.
Moodley, Y.P. The role of inducible nitric oxide in health and disease. Curr. Diagn. Pathol., 2002, 8, 297-304.
Alderton, W.K.; Cooper, C.E.; Knowles, R.G. Nitric oxide synthases: Structure, function and inhibition. Biochem. J., 2001, 357, 593-615.
Cedergren, J.; Follin, P.; Forslund, T.; Lindmark, M.; Sundqvist, T.; Skogh, T. Inducible Nitric Oxide Synthase (NOS II) is constitutive in human neutrophils. APMIS, 2003, 111, 963-968.
Förstermann, U.; Sessa, W.C. Nitric oxide synthases: Regulation and function. Eur. Heart J., 2012, 33, 829-837.
Zhang, Y.; Dong, C. Regulatory mechanisms of mitogen-activated kinase signaling. Cell. Mol. Life Sci., 2007, 64, 2771-2789.
Pearson, G.; Robinson, F.; Gibson, T.B.; Xu, B.; Karandikar, M.; Berman, K.; Cobb, M.H. Mitogen-Activated Protein (MAP) kinase pathways: Regulation and physiological functions. Endocr. Rev., 2001, 22, 153-183.
Symons, A.; Beinke, S.; Ley, S.C. MAP kinase kinase kinases and innate immunity. Trends Immunol., 2006, 27, 40-48.
Karin, M.; Liu, Z.; Zandi, E. AP-1 function and regulation. Curr. Opin. Cell Biol., 1997, 9, 240-246.
Whitmarsh, A.J.; Davis, R.J. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J. Mol. Med. , 1996, 74, 589-607.
Wu, Z.H.; Miyamoto, S. Many faces of NF-κB signaling induced by genotoxic stress. J. Mol. Med. , 2007, 85, 1187-1202.
Hayden, M.S.; Ghosh, S. Signaling to NF-κB. Genes Dev., 2004, 18, 2195-2224.
Nishikori, M. Classical and alternative NF-κB activation pathways and their roles in lymphoid malignancies. J. Clin. Exp. Hematopathol., 2005, 45, 15-24.
Perkins, N.D. Integrating cell-signaling pathways with NF-κB and IKK function. Mol. Cell. Biol., 2007, 8, 49-62.
Tam, A.B.; Mercado, E.L.; Hoffmann, A.; Niwa, M. ER stress activates NF-κB by integrating functions of basal IKK activity, IRE1 and PERK. PLoS One, 2012, 7, e45078.
[ journal.pone.0045078]
Foster, F.M.; Traer, C.J.; Abraham, S.M.; Fry, M.J. The phosphoinositide (PI) 3-kinase family. J. Cell Sci., 2003, 116, 3037-3040.
Franceschelli, S.; Pesce, M.; Ferrone, A.; Gatta, D.M.; Patruno, A.; Lutiis, M.A.; Quiles, J.L.; Grilli, A.; Felaco, M.; Speranza, L. Biological effect of licochalcone C on the regulation of PI3K/Akt/ eNOS and NF-κB/iNOS/NO signaling pathways in H9c2 cells in response to LPS stimulation. Int. J. Mol. Sci., 2017, 18, 690.
Hanada, M.; Feng, J.; Hemmings, B.A. Structure, regulation and function of PKB/AKT-a major therapeutic target. Biochim. Biophys. Acta, 2004, 1697, 3-16.
Jakubowicz-Gil, J. Inhibitors of PI3K-Akt/PKB-mTOR pathway in glioma therapy. Post. Biol. Kom., 2009, 36, 189-201.
Koyasu, S. The role of PI3K in immune cells. Nat. Immunol., 2003, 4, 313-319.
Ihle, J.N. The Stat family in cytokine signaling. Curr. Opin. Cell Biol., 2001, 13, 211-217.
Levy, D.E.; Darnell, J.E. Stats: Transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol., 2002, 3, 651-662.
Murray, P.J. The JAK-STAT signaling pathway: Input and output integration. J. Immunol., 2007, 178, 2623-2629.
Yamaoka, K.; Saharinen, P.; Pesu, M.; Holt, V.E.; Silvennoinen, O.; O’Shea, J.J. The Janus kinases (Jaks). Genome Biol., 2004, 5, 253-259.
Richard, A.J. Stephens, J.M. The role of JAK-STAT signaling in adipose tissue function. Biochim. Biophys. Acta, 2014, 1842, 431-439.
Kiu, H. Nicholson, S.E. Biology and significance of the JAK/ STAT signalling pathways. Growth Factors, 2012, 30, 88-106.
Ratajczak-Wrona, W.; Jablonska, E.; Jablonski, J.; Marcinczyk, M. Induction of expression of iNOS by N-nitrosodimethylamine (NDMA) in human leukocytes. Immunopharm. Immunot., 2009, 31, 661-668.
Ratajczak-Wrona, W.; Jablonska, E.; Garley, M.; Jablonski, J.; Radziwon, P. Role of the JNK signalling pathway in the induction of iNOS expression in neutrophils and mononuclear cells exposed to N-nitrosodimethylamine (NDMA). APMIS, 2011, 119, 431-441.
Stempin, C.C.; Garrido, V.V.; Dulgerian, L.R.; Cerban, F.M. Cruzipain and SP600125 induce p38 activation, alter NO/arginase balance and favor the survival of Trypanosoma cruzi in macrophages. Acta Trop., 2008, 106, 119-127.
Ratajczak-Wrona, W.; Jablonska, E.; Garley, M.; Jablonski, J.; Radziwon, P. Role of ERK1/2 kinase in the expression of iNOS by NDMA in human neutrophils. Indian J. Exp. Biol., 2013, 51, 73-80.
Kang, K.W.; Choi, S.Y.; Cho, M.K.; Lee, C.H.; Kim, S.G. Thrombin induces nitric-oxide synthase via Galpha12/13-coupled protein kinase C-dependent I-kappaBalpha phosphorylation and JNK-mediated I-kappaBalpha degradation. J. Biol. Chem., 2003, 278, 17368-17378.
Zhongyan, W.; Peter, B. Salicylate inhibition of extracellular signal-regulated kinases and inducible nitric oxide synthase. Hypertension, 1999, 34, 1259-1264.
Ratajczak-Wrona, W.; Jablonska, E.; Garley, M.; Jablonski, J.; Radziwon, P.; Iwaniuk, A. The role of MAP kinases in the induction of iNOS expression in neutrophils exposed to NDMA: The involvement transcription factors. Adv. Med. Sci., 2013, 58, 265-273.
Ratajczak-Wrona, W.; Jablonska, E.; Garley, M.; Jablonski, J.; Radziwon, P.; Iwaniuk, A. Role of AP-1 family proteins in regulation of inducible Nitric Oxide Synthase (iNOS) in human neutrophils. J. Immunotoxicol., 2013, 10, 32-39.
Mollinedo, F.; Vaquerizo, M.J.; Naranjo, J.R. Expression of c-jun, jun B and jun D proto-oncogenes in human peripheral-blood granulocytes. Biochem. J., 1991, 273, 477-479.
Kanai, K.; Asano, K.; Hisamitsu, T.; Suzaki, H. Suppression of matrix metalloproteinase-9 production from neutrophils by a macrolide antibiotic, roxithromycin, in vitro. Mediators Inflamm., 2004, 13, 313-319.
Marks-Konczalik, J.; Chu, S.C.; Moss, J. Cytokine mediated transcriptional induction of the human inducible nitric oxide synthase gene requires both activator protein 1 and nuclear factor kB-binding sites. J. Biol. Chem., 1998, 273, 22201-22208.
Ratajczak-Wrona, W.; Jablonska, E.; Garley, M.; Jablonski, J.; Radziwon, P.; Iwaniuk, A.; Grubczak, K. PI3K-Akt/PKB signaling pathway in neutrophils and mononuclear cells exposed to N-Nitrosodimethylamine. J. Immunotoxicol., 2014, 11, 231-237.
Díaz-Guerra, M.J.M.; Castrillo, A.; Martín-Sanz, P.; Boscá, L. Negative regulation by phosphatidylinositol 3-kinase of inducible nitric oxide synthase expression in macrophages. J. Immunol., 1999, 162, 6184-6190.
Ratajczak-Wrona, W.; Jablonska, E.; Garley, M.; Jablonski, J.; Radziwon, P.; Iwaniuk, A. Activation of the JAK/STAT pathway in human neutrophils by NDMA. Turkish. J. Biol., 2013, 37, 629-637.
Schmidt, N.; Pautz, A.; Art, J.; Rauschkolb, P.; Jung, M.; Erkel, G.; Goldring, M.B.; Kleinert, H. Transcriptional and post-transcriptional regulation of iNOS expression in human chondrocytes. Biochem. Pharmacol., 2010, 79, 722-732.

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Article Details

Year: 2019
Page: [194 - 199]
Pages: 6
DOI: 10.2174/1570180815666180426121503
Price: $65

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