Immunomodulatory effects of cigarette smoke

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Abstract

Cigarette smoke is a major health risk factor which significantly increases the incidence of diseases including lung cancer and respiratory infections. This increased susceptibility may result from cigarette smoke-induced impairment of the immune system. While the acute effects of cigarette smoke on the immune system are less clear, chronic exposure to cigarette smoke or nicotine causes T cell unresponsiveness. This apparent T cell anergy may account for or contribute to the immunosuppressive and anti-inflammatory properties of cigarette smoke/nicotine. Nicotine-induced immunosuppression may result from its direct effects on lymphocytes, indirectly through its effects on the neuroendocrine system, or both.

Introduction

Tobacco smoke is a complex mixture of thousands of different chemicals many of which have toxic and/or carcinogenic activity (Stedman, 1968; Hoffmann et al., 1979). The constituents of mainstream tobacco smoke (smoke drawn into the mouth during puffs) are principally encountered by smokers; environmental tobacco smoke (smoke originating mostly from the smoldering end of a cigarette between puffs and exhaled mainstream tobacco smoke) is responsible for involuntary or `passive' smoking by non-smokers (US Department of Health and Human Services, 1993).

Bioassays using tobacco smoke have shown that the majority of genotoxic and carcinogenic substances as well as nicotine are present in the particulate phase (material from cigarette smoke retained by the Cambridge filter comprised mostly of particles >0.1 μm diameter) of mainstream cigarette smoke (Dube and Green, 1982). The vapor phase (substances that pass through the Cambridge filter), has several known carcinogens, but has not been shown to be tumorigenic in inhalation assays (Hoffmann and Wynder, 1986).

Interest in understanding the mechanism of action by which cigarette smoke/nicotine influences the immune system stems from the recognition that tobacco smoking is a major cause of mortality and morbidity, responsible for over 400,000 deaths yr−1 in the United States; the direct health care costs related to cigarette smoking exceed US$50 billion yr−1 (US Department of Health and Human Services, 1994). Tobacco smoke has been demonstrated to significantly increase the incidence of heart disease, cancer at various sites, in particular the lung, and susceptibility to respiratory diseases (US Department of Health, Education and Welfare, 1979). Moreover, some recent data suggest that smoking may be a risk factor in faster development of AIDS in HIV-1-seropositive individuals, higher susceptibility of AIDS patients to develop Pneumocytis carinii infections, and higher frequency of transmission of AIDS from smoking mothers to their offspring (Burns et al., 1991; Nieman et al., 1993; Burns et al., 1994).

In recent years, there has been growing concern that non-smokers may also be at risk for some of the cigarette smoke-associated diseases as a result of involuntary exposure to environmental tobacco smoke. Despite quantitative differences, the chemical composition of environmental tobacco smoke is very similar to mainstream tobacco smoke and may predispose people to lung cancer and increased risks for lower respiratory tract infections (US Department of Health and Human Services, 1993).

Increased susceptibility of smokers to respiratory tract diseases and cancer may reflect cigarette smoke-induced impairment of the immune system (Holt and Keast, 1977). It has recently been postulated that atherosclerosis, which is significantly more prevalent in smokers, may also be an immunologically mediated disease (Wick et al., 1995). Thus, most of the deleterious effects of tobacco smoke on human health may reflect the adverse effects of tobacco smoke on the immune system. Immunosuppressive properties of cigarette smoke have been well established in a variety of experimental animal models and humans (Johnson et al., 1990; Sopori et al., 1994). However, the manner in which cigarette smoke affects the immune system is not clearly understood. There is increasing evidence that nicotine, a major component in cigarette smoke, may significantly contribute to cigarette smoke-induced immunosuppression (Sopori et al., 1993). This review will mainly focus on the effects of various components of cigarette smoke on the immune system and potential mechanisms through which cigarette smoke may affect the immune response.

Section snippets

Effects of cigarette smoke on the human immune system

The possibility that human diseases associated with cigarette smoke reflect the effects of tobacco smoke on the immune system was recognized in the 1960s (reviewed in Holt and Keast, 1977). Since then, a large body of evidence tends to support this inference (Holt, 1987; Johnson et al., 1990; Sopori et al., 1994). Human smokers are more likely to develop influenza and have lower antibody titers to influenza virus (Finklea et al., 1969; Aronson et al., 1982; Kark et al., 1982). Prenatal and

Effects of cigarette smoke on the immune system: animal studies

As in human studies, immunologic changes associated with cigarette smoke exposure are modified by several factors including the level and duration of exposure to cigarette smoke, tar and nicotine content of the smoke, and the species of the animal tested. Most of the animal studies have used rodents, especially rats and mice. There are inherent drawbacks in most rodent studies, because it is impractical to precisely replicate the characteristics patterns of human smoking. Thus, unlike humans,

Components of cigarette smoke that may affect the immune response

The observation that exposure to smoke from high-tar high-nicotine cigarettes is more immunosuppressive than the smoke from low-tar low-nicotine cigarettes (Holt et al., 1976), suggests that tar and nicotine may be important immunotoxic components within cigarette smoke. Most of the tar, nicotine, and genotoxicity of cigarette smoke is associated with the particulate phase of cigarette smoke (Hoffmann et al., 1979; Hoffmann and Wynder, 1986). Chronic exposure of rats to the vapor phase of

Mechanism(s) of cigarette smoke-induced changes in the immune system

From the above discussion, it is clear that chronic exposures to cigarette smoke suppress the antibody response, and nicotine may significantly contribute to this immunosuppression. Xenobiotics have been shown to affect immunoregulation by several mechanisms and cigarette smoke/nicotine could potentially affect the immune system by the following mechanisms.

Conclusion

Based on available scientific evidence, chronic exposure to mainstream and sidestream tobacco smoke appears to impair the immune system in man and experimental animals. In addition, both mainstream and sidestream tobacco smoke may cause airway hyperreactivity. Cigarette smoke is a complex mixture of thousands of different chemical compounds and, depending on the dose and time period of exposure, some of these may cause immunostimulation or immunosuppression (Sopori et al., 1994). Recent

Acknowledgements

This work was supported in part by grants from the National Institute of Drug Abuse DA04208 and DA05662. We thank Dr. M.I. Luster (National Institute for Occupational Safety and Health, Morgantown, WV) for his helpful suggestions about the manuscript.

References (112)

  • T. Kishimoto et al.

    Cytokine signal transduction

    Cell

    (1994)
  • E.D. London et al.

    Distribution of cerebral metabolic effects of nicotine in the rat

    Eur. J. Pharmacol.

    (1985)
  • E.D. London et al.

    Autoradiographic localization of [3H]-nicotine binding sites in the rat brain

    Neurosci. Lett.

    (1985)
  • J.S. Mackenzie

    The effects of cigarette smoke on influenza virus, a murine model system

    Life Sci.

    (1976)
  • P. Marrack et al.

    Subversion of immune system by pathogens

    Cell

    (1994)
  • K. Meguro et al.

    Nicotine improves cognitive disturbance in senescence-accelerated mice

    Pharmacol. Biochem. Behav.

    (1994)
  • E.J. Pearce et al.

    Induction of Th2 responses in infectious diseases

    Curr. Opin. Immunol.

    (1995)
  • S.M. Savage et al.

    Effects of cigarette smoke on the immune response: II. chronic exposure to cigarette smoke inhibits surface immunoglobulin-mediated responses in B cells

    Toxicol. Appl. Pharmacol.

    (1991)
  • L.E. Seyler et al.

    The effects of smoking on ACTH and cortisol secretion

    Life Sci.

    (1984)
  • A. Sher et al.

    Immunity to infection

    Curr. Opin. Immunol.

    (1995)
  • J. Sloan-Lancaster et al.

    Partial T cell signaling, altered phospho-ξ and lack of ZAP-70 recruitment in APL-induced T cell anergy

    Cell

    (1994)
  • M.L. Sopori et al.

    Immune responsiveness of monkeys exposed chronically to cigarette smoke

    Clin. Immunol. Immunopathol.

    (1985)
  • M.L. Sopori et al.

    Cigarette smoke causes inhibition of the immune response to intratracheally administered antigens

    Toxicol. Appl. Pharmacol.

    (1989)
  • R.A. Abbud et al.

    Enhanced production of human immunodeficiency virus type-1 by in vitro infected alveolar macrophages from otherwise healthy cigarette smokers

    J. Infec. Dis.

    (1995)
  • A.M. Adesina et al.

    Bronchiolar inflammation and fibrosis associated with smoking

    Am. Rev. Respir. Dis.

    (1991)
  • P. Andersen et al.

    Serum immunoglobulins in smokers and non-smokers

    Clin. Exp. Immunol.

    (1982)
  • M.M. Archuleta et al.

    7,12-dimethylbenz[a]anthracene activates protein–tyrosine kinases Fyn and Lck in the HPB-ALL human T-cell line and increases tyrosine phosphorylation of phospholipase C-γ1, formation of inositol 1,4,5-trisphosphate, and mobilization of intracellular calcium

    Proc. Natl. Acad. Sci. U.S.A.

    (1993)
  • G.W. Arendash et al.

    Improved learning and memory in aged rats with chronic administration of nicotinic receptor agonist GTS-21

    Brain Res.

    (1995)
  • M. Aronson et al.

    Association between cigarette smoking and acute respiratory tract illness in young adults

    JAMA

    (1982)
  • D.J. Ayer et al.

    Effects of tobacco smoke on splenic architecture and weight, during the primary immune response of BALB/c mice

    J. Pathol.

    (1981)
  • S.L. Bahna et al.

    Immunoglobulin E pattern in cigarette smokers

    J. Allergy Clin. Immunol.

    (1983)
  • M.J. Berridge

    Inositol trisphosphate and calcium signaling

    Nature

    (1993)
  • J.E. Blalock

    The immune system, our sixth sense

    Immunologist

    (1994)
  • C.H. Bosken et al.

    Characterization of the inflammatory reaction in the peripheral airways of cigarette smokers using immunocytochemistry

    Am. Rev. Respir. Dis.

    (1992)
  • N. Braubar

    Direct effects of nicotine on the brain, evidence for chemical addiction

    Arch. Environ. Health

    (1995)
  • G.P. Brown et al.

    Cigarette smoking decreases interleukin-1 release by human alveolar macrophages

    Am. J. Physiol.

    (1989)
  • D.N. Burns et al.

    Cigarette smoking, a modifier of human immunodeficiency virus type 1 infection?

    J. AIDS

    (1991)
  • D.N. Burns et al.

    Cigarette smoking, premature rupture of membranes, and vertical transmission of HIV-1 among women with low CD4+ levels

    J. AIDS

    (1994)
  • B. Burrows et al.

    Respiratory disorders and allergy skin test reactions

    Ann. Int. Med.

    (1976)
  • B. Burrows et al.

    The relationship of serum immunoglobulin E to cigarette smoking

    Am. Rev. Respir. Dis.

    (1981)
  • K.A. Byron et al.

    IL-4 production is increased in cigarette smokers

    Clin. Exp. Immunol.

    (1994)
  • J.C. Cambier et al.

    Signal transduction by the B cell antigen receptor and its co-receptors

    Ann. Rev. Immunol.

    (1994)
  • J. Chalmer et al.

    Cell-mediated immune response to transplanted tumors in mice chronically exposed to fresh cigarette smoke

    J. Natl. Cancer Inst.

    (1975)
  • A. Chan et al.

    The role of tyrosine kinases and protein tyrosine phosphatases in the antigen receptor signal transduction

    Ann. Rev. Immunol.

    (1994)
  • D.E. Clapham

    Calcium signaling

    Cell

    (1995)
  • M. Clerici et al.

    Changes in interleukin-2 and interleukin-4 produced in asymptomatic, human immunodeficiency virus-seropositive individuals

    J. Clin. Invest.

    (1993)
  • K.J.P. Craib et al.

    The effects of cigarette smoking on lymphocyte subsets and progression to AIDS in a cohort of homosexual men

    Clin. Invest. Med.

    (1996)
  • P.E. Cryer et al.

    Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated hemodynamic and metabolic events

    N. Engl. J. Med.

    (1976)
  • R. Doll et al.

    Mortality in relation to smoking, 20 years observation on male British doctors

    Br. Med. J.

    (1976)
  • J.M. Drazen et al.

    Sorting out the cytokines of asthma

    J. Exp. Med.

    (1996)
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