Immunological Effects of Tobacco Smoking in “Healthy” Smokers

Figures & data

Table 1 Smoking effects on humoral immunity

Author	Result	Comment
Secretory Response
Bennet (25)	1. sIgA—no difference	1. Seen in moderate smokers (20 cigs/20 yrs)
	2. Low sIgA	2. Highly defined smokers (20 cigs/40yrs)
Hersey (26)	Decreased sIgA
Jedrychowski (27)	Decreased sIgA and serum IgA
Barton (28)	Decreased sIgA Increased IgM in smokers
Ussher (29)	Decreased sIgA	Acute response (1 day), which returned to normal by 1 week after stopping smoking.
Olson (30)	sIgA—no difference	Evaluated effect of nicotine gum.
Griesel (31)	Decreased sIgA	Seen in first 2 weeks then returned to normal after stopping smoking.
Evans (32)	Decreased sIgA	Smoking is an independent predictor
Serum Immunoglobulin
Gerrard (42)	Decreased IgG Increased IgE	No difference for IgA, IgD, and IgM in smokers compared to non-smokers
Graswinckel (73)	No difference	Smoking significantly related to lower IgG and IgG2 in periodontitis
Gyllen (45)	Decreased IgG and IgG2	No effect of smokeless tobacco and nicotine
Qvarfordt (74)	Decreased IgG and IgG2	Seen in asymptomatic and smokers with chronic bronchitis. Chronic bronchitis patients had lower IgG4 than non-smokers.
Moszczynski (43, 44)	Decreased IgG, IgA, IgM	Long term (> 10 years) smoking effect
Wolfe (52)	Decreased IgA and IgG	No change in IgM

Table 2 Cytokine families and members ([53])

Family	Members	Principal Source	General Effect(s)
IL-1	IL-1α /IL-1F1 IL1-β /IL1-F2 IL-1 receptor-antagonist/IL-1F3 IL-18/IL-1F4	Macrophages, antigen presenting cells Dendritic cells mononuclear/macrophages	Primarily proinflammatory cytokines; initiation of COX-2, type 2 phospholipase A and inducible nitric oxide synthase (iNOS). Increase expression of adhesion molecules; angiogenic factor; aids differentiation of marrow stem cells in myeloid series. IL-18 induces INFγ, IL-4, IL-5 and IL-13 in concert with other factors.
IL-2/IL-4	IL-2 IL-3 IL-4 IL-5 GM-CSF	TH-1 cells, NK cells T-cells, macrophages TH-2 cells, mast cell TH-2 cells, mast cells T-cells, macrophages, fibroblasts	Pleiotrophic actions including augment proliferation of T-cells, role in activation induced cell death, promote growth and differentiation B-cells, augment NK-cell cytolytic activity, induces lymphokine activated killer activity and proliferation of large granular lymphocytes; induces IL-2 receptor; and stimulate monocyte cytotoxicity, GM-CSF, IL-1β and IL-6 mRNA and protein. IL-3 has very broad cell targets and stimulates generation and differentiation of dendritic, macrophages, neutrophils, eosinophils, basophils, mast cells, megakaryocytes and erythroid cells. IL-4 induces biological functions on dendritic cells and T-cells. IL-5 eosinophil hematopoietic growth factor, B-cell growth and differentiation factor GM-CSF stimulates growth of multiple myeloid cells, augments function of phagocytes, macrophages, dendritic cells and eosinophils
IL-6/IL-12	IL-6 IL-12 IL-23 IL-27	TH-2, antigen processing cells, somatic cells B-cells, macrophages APC, dendritic cells, macrophages, T-cells, monocytes TH-1, monocytes, macrophages Monocytes, DC, placenta	IL-6 pleiotropic cytokine that regulates immune reactivity, acute-phase response, inflammation, oncogenesis and hematopoiesis. IL-12 pleiotropic immuno-modulation TH-1 response inducer, enhance B-cell survival but suppresses IgE synthesis. IL-23 IL-12 like-effects, activate memory T-cells, increase acute phase proteins, IL-1, TNFα, INFγ. IL-27 function not fully clear; role inducing TH1 immunity
	IL-7	Thymic, bone marrow and hepatic stroma, smooth muscle, fibroblast, dendritic cells, endothelial cells	Growth and differentiation factor for γ δ T-cells, B-cell development, promotes effector functions of T-cells, NK cells, monocytes.
	IL-9 IL-11, IL-13, IL-14 IL-16	T-cells Fibroblasts, epithelial cells, chondrocytes, synoviocytes, endothelial cells, osteoblasts T-cells, NK, basophils, eosinophils, mast cells, dendritic cells T-cells, mast cells eosinophils, DC, B-cells, bronchial epithelial, fibroblast	IL-9 T-cell and mast cell growth factor; synergize B-cell IgE and IgG production; modest hematopoietic activity. IL-11 hematopoietic (thrombopoiesis) cytokine, protects and restores gastrointestinal mucosa; immuno-modulating agent, affects bone metabolism. IL-13 immuno-modulation B-cells with role in effector phase of allergic and asthma response protects from helminthes infections. IL-14 is high molecular weigh B-cell growth factor. IL-16 T cell chemoattractant, proliferation and differentiation.
IL-10	IL-10 IL-19 IL-20 IL-22 IL-24 IL-26 IL-28 (IFNλ 2, 3) IL-29 (IFNλ 1)	TH-2 cells, activated T-cells and B-cells, monocytes/macrophages, mast cells, keratinocytes	Conti et al([75]) Regulator of immune response; turns off T-cell cytokine production; inhibits monocyte/macrophage production of IL-α 1, LI-1β, IL-6, IL-8, IL-12, TNF, GM-CSF, INF and other cellular functions. IL-19 induce IL-10([76]). IL-20 promotes keratinocyte proliferation. IL-22 promotes acute phase proteins production, inhibit IL-4 production. IL-24 suppresses tumor growth; linked to wound healing. IL-26 function not defined.
IL-15	IL-15 IL-21	Macrophages, antigen presenting cells CD4 T-cells	IL-15 shares activity with IL-2, stimulates T-cells, B-cells, NK cells, monocytes, eosinophils, neutrophils, mast cells, non-immune cells; pivotal role in immune response, graft rejection and autoimmunity IL-21 immunoregulatory function for B-cells, T-cells; enhance NK cell effector function
IL-17	IL-17 IL-25	memory T-cells	Mediate the stimulation of neutrophil mobilization, induces many other cells to produce various cytokines. IL-25 increase cytokines, IgG1 IgE and IgE, eosinophilia.
Newer interleukins	IL-30 IL-31 IL-32	T-cells Mononuclear, NK cells	P-28 subunit of IL-27 Induce chemokines Induces TNFα, IL-8 and MIP-2CXCL-2
Type I Interferons (IFN) Type II IFN	IFN-α IFN-β IFN-ε IFN-κ IFN-ω INF-τ IFNλ IFNδ IFN-γ	Macrophage and neutrophils TH-1, NK cells, fibroblasts keratinocytes leukocyte Trophoblast Dendritic cells T-cells, NK cells	Anti-viral, pro-apoptotic, proliferation and maturation of NK cells, induce IL-15 and IL-10, inhibit T-cell migration, and promote T-cell survival. Promotes innate and adaptive immunity to infectious agents (anti-viral) and tumors; promotes antigen processing and presentation; regulates B-cell functions; role in TH1 development.
Tumor necrosis factors	TNF-α TNF-β /LT-α LT-β Fas ligand CD-40 ligand TRAIL BAFF APRIL RANK LIGHT	Various immune and non-immune cells	Pleiotropic pro-inflammatory cytokine with multiple biological effects at cellular and organ level.
TGF-β	TGF-β Bone morphogenetic proteins Inhibins Activins	Immune and non-immune cells	Inhibitor of cell proliferation, immunosuppressor, pro-inflammatory, anti-inflammatory, tissue remodeling
Chemokines	CXC subfamily (CXCL1-16) CC subfamily (CCL1-28) C subfamily (CL1 / Lymphotactin) CX3C subfamily (CX3CL1 / Fractalkin) IL-8 (CXCL8)	All somatic cells Peripheral blood mononuclear, T-cells, neutrophil, endothelial, fibroblast, epithelial, NK cells	Pro-inflammatory mediators with chemotactic activity for spectrum of cells

Table 3 Summary of cytokine changes found in healthy smokers

Specimen	Cytokine	Smoking effect	Comments
BALF
	IL-1	Less IL-1	Yamaguchi ([51]) Stimulated alveolar macrophages
	IL-2 IL-4 IFN-γ	Decreased Indeterminate Decreased	Hagiwara ([77]) Mitogen stimulate cells; heavy smokers
	IL-1β IL-6 IL-8 MCP	Increased Increased Increased Increased	Kuschner ([58]) Study demonstrated dose response effect of smoking in cells counts as well as cytokines
	IL-1ra, IL-6, IL-8 TNF and IL-1β	Decreased Decreased Decreased No difference	Mikuniya ([59]) BALF stimulated macrophages. Il-1ra and IL-6 most prominent changes
	IL-6 IL-8 TNF	Decreased No difference Decreased	McCrea ([57]) LPS stimulated macrophages
	IL-1β IL-6 IL-8 TNF-α IFN-γ	Decreased Decreased No difference Decrease Decrease	Alveolar macrophages
	IL-1 IL-6	Decreased Less	Soliman ([63]) LPS induced Intracellular IL-1 high; undetected IL-6 in cell in both
	IL-8	Increased in BALF, Decreased	Ohta ([60]) Stimulated alveolar macrophages
	IL-8	No difference/ increase in acute smokers	Morrison ([62]) Neutrophil source
	IL-16	Increased	Laan ([65]); Smokers > Non-smokers; no difference between types of smokers. Negative correlation with CD 4 number of cells
Sputum
	IL-10	Decreased	Takanashi ([68])
	TNF-α sTNF-R IL-8	No difference Increased Increased	Vernooy ([66]) Sputa had more inflammatory cells and less macrophages in diseased vs. healthy smokers
	IL-18	Decreased	McKay ([69])
Peripheral blood
	IL-4 IFN-γ	No difference between smokers and non-smokers	Majori ([70])
	IL-4 IFN-γ	Increased No difference	Byron ([71]) phytohemagglutinin stimulated PBMC
	IL-6 TNF-α	Less	Wirtz ([72]) LPS stimulated WBC
	IL-10	Less Decreased	Karjalinen ([56]) IL-10 haplotype assoc with smoking and lung impairment, and regulation of IgE production. They posed the gene may differentially respond to disease vs. normal/control situation.

Vilcek J. The cytokines: An overview. The Cytokine Handbook, Fourth edition, A G Thomson, M T Lotze. Elsevier Science, London 2003

 Google Scholar

Conti P, Kempuraj D, Frydas S, Kandere K, et al. IL-10 subfamily members: IL-19, IL-20, IL-22, IL-24 and IL-26. Immunol Lett 2003; 88: 171–174

 PubMed Web of Science ®Google Scholar

Jordan W J, Eskdale J, Boniotto M, Lennon G P, et al. Human IL-19 regulates immunity through auto-induction of IL-19 and production of IL-10. Eu J Immunol 2005; 35: 1576–1582

 PubMed Web of Science ®Google Scholar

Yamaguchi E, Okazaki N, Itoh A, Abe S, et al. Interleukin 1 production by alveolar macrophages is decreased in smokers. Am Rev Respir Dis 1989; 140: 397–402

 PubMed Web of Science ®Google Scholar

Hagiwara E, Takahashi K, Okubo T, Ohno S, et al. Cigarette smoking depletes cells spontaneously secreting Th 1 cytokines in human airway. Cytokine 2001; 14: 121–126

 PubMed Web of Science ®Google Scholar

Kuschner W G, D'Alessandro A, Wong H, Blanc P K. Dose dependent cigarette smoking related inflammatory responses in healthy adults. Eur Respir J 1996; 9: 1989–1994

 PubMed Web of Science ®Google Scholar

Mikuniya T, Nagai S, Tsutsumi T, Morita K, et al. Proinflammatory or regulatory cytokines released from BALF macrophages of healthy smokers. Respiration 1999; 66: 419–426

 PubMed Web of Science ®Google Scholar

McCrea K A, Ensor J E, Nall K, Bleecker E R, Hasday J D. Altered Cytokine regulation in the lungs of cigarette smokers. Am J Respir Crit Care Med 1994; 150: 696–703

 PubMed Web of Science ®Google Scholar

Soliman D M, Twigg H L, III. Cigarette smoking decreases bioactive interlieukin-6 secretion by alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 1992; 63: L471–L478

 Google Scholar

Ohta T, Yamashita N, Maruyama M, Sugiyama E, Kobayashi M. Cigarette smoking decreases ineerleukin-8 secretion by human alveolar macrophages. Respir Med 1998; 92: 922–927

 PubMed Web of Science ®Google Scholar

Morrison D, Strieter R M, Donnelly S C, Burdick M D, et al. Neutrophil chemokines in bronchoalveolar lavage fluid and leukocyte conditioned medium fro nonsmokers and smokers. Eur Respir J 1998; 12: 1067–1072

 PubMed Web of Science ®Google Scholar

Laan M, Qvarfordt I, Riise G C, Andersson A A. Increased levels of interleukin-16 in the airways of tobacco smokers: relationship with peripheral blood T lymphocytes. Thorax 1999; 54: 911–916

 PubMed Web of Science ®Google Scholar

Takanashi S, Hasegawa Y, Kanehira Y, Yamamoto K, et al. Interleukin-10 level in sputum is reduced in bronchial asthma, COPD and in smokers. Eur Respir J 1999; 14: 309–314

 PubMed Web of Science ®Google Scholar

Vernooy J H, Kucukayacan M, Jacobs J A, Chavannes N H, et al. Local and systemic inflammation in patients with chronic obstruction pulmonary disease. Am J Respir Crit Care Med 2002; 166: 1218–1224

 PubMed Web of Science ®Google Scholar

McKay A, Komai-Koma M, MacLeod K J, Campbell C C, et al. Interleukin-18 levels in induced sputum are reduced in asthmatic and normal smokers. Clin Exp Allergy 2004; 34: 904–910

 PubMed Web of Science ®Google Scholar

Majori M, Corradi M, Caminati A, Cacciani G, et al. Predominate Th-1 cytokine pattern in peripheral blood from subjects with chronic obstructive pulmonary disease. J Allergy Clin Immunol 1999; 103: 458–462

 PubMed Web of Science ®Google Scholar

Byron K A, Varigos G A, Wootton A M. IL-4 production is increased in cigarette smokers. Clin Exp Immunol 1994; 95: 333–336

 PubMed Web of Science ®Google Scholar

Wirtz P H, von Kanel R, Kunz-Ebrecht S, Ehlert U, Fischer J E. Enhanced glucocorticoid sensitivity of cytokine release from circulating leukocytes stimulated with lipopolysaccharide in healthy male smokers. Brain Behav Immun 2004; 18: 536–543

 PubMed Web of Science ®Google Scholar

Karjalainen J, Julkkonen J, Hurme M, Joos L, Pare P K, Sandford A. IL-1 haplotypes and lung function decline. Thorax 2002; 57: 561–562

 PubMed Web of Science ®Google Scholar