Nicotine Modulates the Release of Inflammatory Cytokines and Expression of TLR2, TLR4 of Cord Blood Mononuclear Cells

  • Laya Takbiri Osgoei Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
  • Kazem Parivar Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
  • Marzieh Ebrahimi Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran, Iran
  • Esmaeil Mortaz Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran AND Department of Immunology, Faculty of Medicine, Shahid Beheshti University of  Medical Sciences, Tehran, Iran
Keywords: Cytokines, Nicotine, TLRs, Umbilical mononuclear cells


The underlying mechanisms of how nicotine affects cord umbilical cells remain largely elusive. Nicotine rapidly crosses the blood-brain barrier (10 to 20 s) and binds to nicotinic acetylcholine receptors (nAChRs). Nicotine considered as a major compound found in cigarette smoke and the mechanism of nicotine action in immune response is not well understood. Cigarette smoke well known by activation of toll like receptors (TLRs) especially TLR4 and 9 which stimulates the immune response by induction of releases of cytokines mainly CXCL-8 which in turn triggers lungs reactions specially induction of neutrophils recruitments. In this study we isolated human umbilical mononuclear cells (UCBMC) from umbilical cord blood and exposed to the nicotine for detection any cytokines and TLRs modulation. We have found that nicotine (at concentration 0.01µM) induced release of TNF-a and IL-6 but not CXCL-8 production. Besides we have shown that nicotine did not effect on TLR4 surface expression however up-regulated the TLR2 surface expression. Moreover expression of CD11a and CXCR4 after nicotine incubation was upregulated as demonstrated by flow cytometry analysis, These data indicated that nicotine by stimulation of inflammatory cytokines induces immune response. The present study provides evidence that nicotine selectively regulates the release of cytokines and expression of TLRs. Further studies are needed to exploring details of its effects and signaling.


1. Craig WY, Palomaki GE, Haddow JE. Cigarette smoking and serum lipid and lipoprotein concentrations: an analysis of published data. Bmj 1989; 298(6676):784 –8.

2. Hartz AJ, Anderson AJ, Brooks HL, Manley JC, Parent GT, Barboriak JJ. The association of smoking with cardiomyopathy. N Engl J Med 1984; 311(19):1201–6.

3 Karimi K, Sarir H, Mortaz E, Smit JJ, Hosseini H, de Kimpe S, et al. Toll-like receptor-4 mediates cigarette smoke-induced cytokine production by human macrophages. Respir Res 2006; 7:66.

4. Mortaz E, Adcock IM, Ito K, Kraneveld AD, Nijkamp FP, Folkerts G. Cigarette smoke induces CXCL8 production by human neutrophils via activation of TLR9 receptor. Eur Respir J 2010; 36(5):1143-54.

5. Mortaz E, Henricks PA, Kraneveld AD, Givi ME, Garssen J, Folkerts G. Cigarette smoke induces the release of CXCL-8 from human bronchial epithelial cells via TLRs and induction of the inflammasome. Biochim Biophys Acta 2011; 1812(9):1104-10.

6. Mortaz E, Lazar Z, Koenderman L, Kraneveld AD, Nijkamp FP, Folkerts G. Cigarette smoke attenuates the production of cytokines by human plasmacytoid dendritic cells and enhances the release of IL-8 in response to TLR-9 stimulation. Respir Res 2009; 10:47.

7. Paul P. Lau, Lan Li, Aksam J. Merched, Alan L. Zhang, Kerry W.S. Ko, Lawrence Chan. Nicotine Induces Proinflammatory Responses in Macrophages and the Aorta Leading to Acceleration of Atherosclerosis in Low-Density Lipoprotein Receptor-/- Mice. Arterioscler Thromb Vasc Biol 2006; 26(1):143-9.

8. Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 2004; 10(11):1216–21.

9. Saeed RW, Varma S, Peng-Nemeroff T, Sherry B, Balakhaneh D, Huston J, et al. Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation. J Exp Med 2004; 201(7):1113–23.

10. Guinet E, Yoshida K, Nouri-Shirazi M. Nicotine environment affects the differentiation and functional maturation of monocytes derived dendritic cells (DCs). Immunol Lett 2004; 95(1):45–55.

11. Vassallo R, Tamada K, Lau JS, Kroening PR, Chen L. Cigarette smoke extract suppresses human dendritic cell function leading to preferential induction of Th-2 priming. J Immunol 2005; 175(4):2684–91.

12. Suzuki J, Bayna E, Molle ED, Lew WYW. Nicotine inhibits cardiac apoptosis induced by lipopolysaccharide in rats. J Am Coll Cardiol 2003; 41(3):482–7.

13. Zhang S, Day INM, Te S. Microarray analysis of nicotine-induced changes in gene expression in endothelial cells. Physiol Genomics 2001; 5(4):187–92.

14. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation . Nature 2003; 421(6921):384–8.

15. Nizri E, Irony-Tur-Sinai M, Lory O, Orr-Urtreger A, Lavi E, Brenner T. Activation of the cholinergic anti-infl ammatory system by nicotine attenuates neuroinfl ammation via suppres- sion of Th1 and Th17 responses . J Immunol 2009; 183(10):6681–8.

16. Lam DC, Luo SY, Fu KH, Lui MM, Chan KH, Wistuba II, et al. Nicotinic acetylcholine receptor expression in human airway correlates with lung function. Am J Physiol Lung Cell Mol Physiol 2016; 310(3):L232–9.

17. Rehan VK, Liu J, Naeem E, Tian J, Sakurai R, Kwong K, et al. Perinatal nicotine exposure induces asthma in second generation offspring. BMC Med 2012; 10:129.

18. Qiu BS, Cho CH, Ogle CW. Chronic nicotine treatment intensifies gastric ulceration by cold-restraint stress in rats. Agents Actions 1991; 33(3–4):367–70.

19. Sarir H, Mortaz E, Karimi K, Kraneveld AD, Rahman I, Caldenhoven E, et al. Cigarette smoke regulates the expression of TLR4 and IL-8 production by human macrophages. J Inflamm (Lond) 2009; 6:12.

20. Akira S, Takeda K. Toll-like receptor signaling. Nat Rev Immunol 2004; 4(7):499-511.

21. Chow JC, Young DW, Golenbock DT, Christ WJ, Gusovsky F. Toll-like Receptor-4 Mediates Lipopolysaccharide-induced Signal Transduction. J Biol Chem 1999; 274(16):10689–92.

22. Mortazavi SH, Amin R, Alyasin S, Kashef S, Karimi MH, Babaei M, et al. Down-regulation of TLR2, 3, 9 and Signaling Mediators, MyD88 and TRIF, Gene Transcript Levels in Patients with Kawasaki Disease Treated with IVIG. Iran J Allergy Asthma Immunol 2015; 14(2):188-97.

23. Wehby GL, Prater K, McCarthy AM, Castilla EE, Murray JC. The Impact of Maternal Smoking during Pregnancy on Early Child Neurodevelopment. J Hum Cap 2011; 5(2):207–54.

24. Wickström R. Effects of Nicotine During Pregnancy: Human and Experimental Evidence. Curr Neuropharmacol 2007; 5(3):213–22.

25. Albaugh G1, Bellavance E, Strande L, Heinburger S, Hewitt CW, Alexander JB. Nicotine induces mononuclear leukocyte adhesion and expression of adhesion molecules, VCAM and ICAM, in endothelial cells in vitro. Ann Vasc Surg 2004; 18(3):302-7.

26. Speer P, Zhang Y, Gu Y, Lucas MJ, Wang Y. Effects of nicotine on intercellular adhesion molecule expression in endothelial cells and integrin expression in neutrophils in, Am J Obstet Gynecol 2002; 186(3):551–6.

27 Jalali M, Nikravesh MR, Moeen AA, Mohammadi S, Karimfar MH. Effects of Maternal Nicotine Exposure on Expression of Collagen Type IV and its Roles on Pulmonary Bronchogenesis and Alveolarization in Newborn Mice. Iran J Allergy Asthma Immunol 2010; 9(3):169-73.

28. Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: Functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 1996; 272(5263):872–7.

29. Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med 1996; 184(3):1101–9.

30. Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F, et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 1996; 382(6594):833–5.

31. Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, Sodroski J, et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 1996; 382(6594):829–33.

32. Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A 1998; 95(16):9448–53.

33. Zeng Z, Shi YX, Samudio IJ, Wang RY, Ling X, Frolova O, et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood 2009; 113(24):6215–24.

34. Petit I, Jin D, Rafii S. The SDF-1-CXCR4 signaling pathway: A molecular hub modulating neo-angiogenesis. Trends Immunol 2007; 28(7):299–307.

35. Viola A, Luster AD. Chemokines and their receptors: Drug targets in immunity and inflammation. Annu Rev Pharmacol Toxicol 2008; 48:171–97.

36. Werner L, Guzner-Gur H, Dotan I. Involvement of CXCR4/CXCR7/CXCL12 Interactions in Inflammatory Bowel Disease. Theranostics. 2013; 3(1):40–6.

How to Cite
Takbiri Osgoei L, Parivar K, Ebrahimi M, Mortaz E. Nicotine Modulates the Release of Inflammatory Cytokines and Expression of TLR2, TLR4 of Cord Blood Mononuclear Cells. Iran J Allergy Asthma Immunol. 17(4):372-378.
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