Cigarette Smoke Constituents and Nicotine Differentially Affect Cytokine Production by Human Macrophages Stimulated by TLR Ligands In Vitro : Considerations for a Standardised Protocol
Restricted accessResearch articleFirst published online July, 2024
Cigarette Smoke Constituents and Nicotine Differentially Affect Cytokine Production by Human Macrophages Stimulated by TLR Ligands In Vitro : Considerations for a Standardised Protocol
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition associated with cigarette (tobacco) smoking. Numerous in vivo animal studies have been conducted to investigate the links between cigarette smoke, nicotine and infection in lung pathology. As an alternative to animal experiments, we used an in vitro system to investigate the effects of cigarette smoke extract (CSE) or nicotine on TNF-α and IL-10 production by monocyte-derived human macrophages. The macrophages were simultaneously stimulated with either poly-IC (as a chemical surrogate for viral infection) or lipopolysaccharide (as a chemical surrogate for Gram-negative bacterial infection). CSE enhanced TNF-α production, whereas nicotine inhibited IL-10 production by the macrophages, particularly when co-stimulated with the microbial chemical surrogates. A system of this type may help to further our understanding of the immunological and inflammatory effects of smoking, without recourse to in vivo studies. Requirements for the optimisation and standardisation of such an in vitro system are also discussed.
BaskaranVMurrayRLHunterA, et al.Effect of tobacco smoking on the risk of developing community acquired pneumonia: A systematic review and meta-analysis. PLoS One2019; 14: e0220204.
3.
GarmendiaJMoreyPBengoecheaJA. Impact of cigarette smoke exposure on host–pathogen interactions. Eur Respir J2012; 39: 467–477.
4.
LaneNRobinsRACorneJ, et al.Regulation in chronic obstructive pulmonary disease: The role of regulatory T-cells and Th17 cells. Clin Sci (Lond)2010; 119: 75–86.
5.
SethiS. Infection as a comorbidity of COPD. Eur Respir J2010; 35: 1209–1215.
6.
FinicelliMDigilioFAGalderisiU, et al.The emerging role of macrophages in chronic obstructive pulmonary disease: The potential impact of oxidative stress and extracellular vesicle on macrophage polarization and function. Antioxidants (Basel)2022; 11: 464.
7.
LuggSTScottAParekhD, et al. Cigarette smoke exposure and alveolar macrophages: Mechanisms for lung disease. Thorax2022; 77: 94–101.
8.
GaschlerGJSkrticMZavitzCC, et al.Bacteria challenge in smoke-exposed mice exacerbates inflammation and skews the inflammatory profile. Am J Respir Crit Care Med2009; 179: 666–675.
9.
GottsJEChunLAbbottJ, et al.Cigarette smoke exposure worsens acute lung injury in antibiotic-treated bacterial pneumonia in mice. Am J Physiol Lung Cell Mol Physiol2018; 315: L25–L40.
10.
GualanoRCHansenMJVlahosR, et al.Cigarette smoke worsens lung inflammation and impairs resolution of influenza infection in mice. Respir Res2008; 9: 53.
11.
KumarSSmith-NorowitzTAKohlhoffS, et al.Exposure to cigarette smoke and Chlamydia pneumoniae infection in mice: Effect on infectious burden, systemic dissemination and cytokine responses: A pilot study. J Immunotoxicol2016; 13: 77–83.
12.
MartinRJWexlerRBDayBJ, et al.Interaction between cigarette smoke and mycoplasma infection: A murine model. COPD2006; 3: 3–8.
13.
MurakamiDKonoMNanushajD, et al.Exposure to cigarette smoke enhances pneumococcal transmission among littermates in an infant mouse model. Front Cell Infect Microbiol2021; 11: 651495.
14.
VossMWonnenbergBHoneckerA, et al.Cigarette smoke-promoted acquisition of bacterial pathogens in the upper respiratory tract leads to enhanced inflammation in mice. Respir Res2015; 16: 41.
15.
ZhangWLinHZouM, et al.Nicotine in inflammatory diseases: Anti-inflammatory and pro-inflammatory effects. Front Immunol2022; 13: 826889.
16.
De CuntoGCavarraEBartalesiB, et al.Alveolar macrophage phenotype and compartmentalization drive different pulmonary changes in mouse strains exposed to cigarette smoke. COPD2020; 17: 429–443.
17.
SubramaniamRMukherjeeSChenH, et al.Restoring cigarette smoke-induced impairment of efferocytosis in alveolar macrophages. Mucosal Immunol2016; 9: 873–883.
18.
MahmoudzadehLAbtahi FroushaniSMAjamiM, et al.Effect of nicotine on immune system function. Adv Pharm Bull2023; 13: 69–78.
19.
ChurgADaiJTaiH, et al.Tumor necrosis factor-α is central to acute cigarette smoke-induced inflammation and connective tissue breakdown. Am J Respir Crit Care Med2002; 166: 849–854.
20.
HigakiMWadaHMikuraS, et al.Interleukin-10 modulates pulmonary neutrophilic inflammation induced by cigarette smoke exposure. Exp Lung Res2015; 41: 525–534.
21.
FernandezABautistaMStanciauskasR, et al.Cell-shaping micropatterns for quantitative super-resolution microscopy imaging of membrane mechanosensing proteins. ACS Appl Mater Interf2017; 9: 27575–27586.
22.
AlkhattabiNToddINegmO, et al.Tobacco smoke and nicotine suppress expression of activating signaling molecules in human dendritic cells. Toxicol Lett2018; 299: 40–46.
23.
AoshibaKNagaiAKonnoK. Nicotine prevents a reduction in neutrophil filterability induced by cigarette smoke exposure. Am J Respir Crit Care Med1994; 150: 1101–1107.
24.
AoshibaKTamaokiJNagaiA. Acute cigarette smoke exposure induces apoptosis of alveolar macrophages. Am J Physiol Lung Cell Mol Physiol2001; 281: L1392–L1401.
25.
BernhardDHuckCWJakschitzT, et al.Development and evaluation of an in vitro model for the analysis of cigarette smoke effects on cultured cells and tissues. J Pharmacol Toxicol Methods2004; 50: 45–51.
26.
LiuXConnerHKobayashiT, et al. Cigarette smoke extract induces DNA damage but not apoptosis in human bronchial epithelial cells. Am J Respir Cell Mol Biol2005; 33: 121–129.
27.
MianMFLauzonNMStampfliMR, et al.Impairment of human NK cell cytotoxic activity and cytokine release by cigarette smoke. J Leukocyte Biol2008; 83: 774–784.
28.
MianMFPekEAMossmanKL, et al.Exposure to cigarette smoke suppresses IL-15 generation and its regulatory NK cell functions in poly I:C-augmented human PBMCs. Mol Immunol2009; 46: 3108–3116.
29.
StringerKATobiasMO’NeillHC, et al.Cigarette smoke extract-induced suppression of caspase-3-like activity impairs human neutrophil phagocytosis. Am J Physiol Lung Cell Mol Physiol2007; 292: L1572–L1579.
30.
SuYCaoWHanZ, et al.Cigarette smoke extract inhibits angiogenesis of pulmonary artery endothelial cells: The role of calpain. Am J Physiol Lung Cell Mol Physiol2004; 287: L794–L800.
31.
WongtrakoolCGroomsKBijliKM, et al.Nicotine stimulates nerve growth factor in lung fibroblasts through an NFκB-dependent mechanism. PLoS One2014; 9: e109602.
JarvisMJBorehamRPrimatestaP, et al.Nicotine yield from machine-smoked cigarettes and nicotine intakes in smokers: Evidence from a representative population survey. J Nat Cancer Inst2001; 93: 134–138.
34.
ChengSFQinXSHanZL, et al.Nicotine exposure impairs germ cell development in human fetal ovaries cultured in vitro. Aging2018; 10: 1556–1574.
35.
DaffnerSDWaughSNormanTL, et al.Nicotine increases osteoblast activity of induced bone marrow stromal cells in a dose-dependent manner: An in vitro cell culture experiment. Global Spine J2012; 2: 153–158.
36.
TintiFSooryM. Mechanisms for redox actions of nicotine and glutathione in cell culture, relevant to periodontitis. SciRep2012; 2: 566.
37.
PurkisSWDrakeLMegerM, et al.A review of the UK methodology used for monitoring cigarette smoke yields, aspects of analytical data variability and their impact on current and future regulatory compliance. Reg Toxicol Pharmacol2010; 56: 365–373.
38.
WrightC. Standardized methods for the regulation of cigarette-smoke constituents. Trends Anal Chem2015; 66: 118–127.
39.
International Organisation for Standardization (ISO). ISO 3308:2012; Routine analytical cigarette smoking machine — Definitions and standard conditions, https://www.iso.org/standard/60404.html (Edition 5 2012, accessed 18 May 2024).
40.
van Zyl-SmitRNBinderAMeldauR, et al.Cigarette smoke impairs cytokine responses and BCG containment in alveolar macrophages. Thorax2014; 69: 363–370.
41.
DemirjianLAbboudRTLiH, et al.Acute effect of cigarette smoke on TNF-α release by macrophages mediated through the erk1/2 pathway. Biochim Biophys Acta2006; 1762: 592–597.
42.
YangS-RWrightJBauterM, et al.Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-B in macrophages in vitro and in rat lungs in vivo: Implications for chronic inflammation and aging. Am J Physiol Lung Cell Mol Physiol2007; 292: L567–L576.
43.
PetrescuFCosmin VoicanSSilosiI. Tumor necrosis factor-α serum levels in healthy smokers and nonsmokers. Int J COPD2010; 5: 217–222.
44.
TanniSEPelegrinoNRGAngeleliAYO, et al.Smoking status and tumor necrosis factor-α mediated systemic inflammation in COPD patients. J Inflamm (Lond)2010; 7: 29.
45.
SolerNEwigSTorresA, et al.Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease. Eur Respir J1999; 14: 1015–1022.
46.
BanerjeeDKhairOAHoneybourneD. Impact of sputum bacteria on airway inflammation and health status in clinical stable COPD. Eur Respir J2004; 23: 685–691.
47.
SelvarajahSToddITighePJ, et al.Multiple circulating cytokines are co-elevated in chronic obstructive pulmonary disease. Mediators Inflamm2016: 3604842.
48.
WangHYuMOchaniM, et al.Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature2003; 421: 384–388.
49.
LauPPLiLMerchedAJ, et al.Nicotine induces proinflammatory responses in macrophages and the aorta leading to acceleration of atherosclerosis in low-density lipoprotein receptor–/– mice. Arterioscler Thromb Vasc Biol2006; 26: 143–149.
50.
SiniavinAEStreltsovaMAKudryavtsevDS, et al.Activation of α7 nicotinic acetylcholine receptor upregulates HLA-DR and macrophage receptors: Potential role in adaptive immunity and in preventing immunosuppression. Biomolecules2020; 10: 507–524.
51.
MartinezFOGordonS. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Rep2014; 6: 13.
52.
LescoatABallerieAAugagneurY, et al.Distinct properties of human M-CSF and GM-CSF monocyte-derived macrophages to simulate pathological lung conditions in vitro: Application to systemic and inflammatory disorders with pulmonary involvement. Int J Mol Sci2018; 19: 894.
53.
YamasakiKEedenSFV. Lung macrophage phenotypes and functional responses: Role in the pathogenesis of COPD. Int J Mol Sci2018; 19.
54.
da SilvaCOGicquelTDanielY, et al.Alteration of immunophenotype of human macrophages and monocytes after exposure to cigarette smoke. Sci Rep2020; 10: 12796.
