Published online June 2, 2008
PEDIATRICS Vol. 121 No. 6 June 2008, pp. e1563-e1569 (doi:10.1542/peds.2007-2795)
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ARTICLE

Effects of Parental Smoking on Interferon {gamma} Production in Children

Gina Tebow, MPHa,b, Duane L. Sherrill, PhDa,b, I. Carla Lohman, MSa, Debra A. Stern, MSa, Anne L. Wright, PhDa,c, Fernando D. Martinez, MDa,c, Marilyn Halonen, PhDa,d and Stefano Guerra, MD, PhDa,b

a Arizona Respiratory Center
c Departments of Pediatrics
d Pharmacology, College of Medicine
b Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona


   ABSTRACT
TOP
 ABSTRACT
Methods
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
OBJECTIVES. Environmental tobacco smoke is associated with several negative health outcomes in children, including an increased susceptibility to infections. One of the postulated mechanisms for these effects is the impairment of the immune system function and/or development. Yet, it remains unknown whether cumulative exposure to parental smoking is associated with altered immune responses in childhood and whether these effects are independent of in utero exposure to maternal smoking. In a population-based birth cohort, we sought to determine the relation of parental smoking, as assessed prospectively since pregnancy, to the child's interferon {gamma} and interleukin 4 production at 11 years of age.

PATIENTS AND METHODS. We used data on 512 children and their parents from the Tucson Children's Respiratory Study cohort. Information on maternal and paternal smoking was collected prospectively by questionnaire, and pack-years for mother, father, and both parents combined were assessed prospectively between the prenatal period and year 11. At age 11 years, children's interferon {gamma} and interleukin 4 production from mitogen-stimulated peripheral blood mononuclear cells was measured.

RESULTS. Children of parents who smoked between the prenatal period and year 11 were more likely to be in lower quartiles of interferon {gamma} production than children of nonsmoking parents. In addition, maternal, paternal, and parental pack-years showed significant inverse dose-response relationships with interferon {gamma} production in the child. These dose-response relationships with interferon {gamma} remained significant for both paternal and parental pack-years among children of mothers who did not smoke during pregnancy, suggesting the existence of specific postnatal effects of environmental tobacco smoke exposure. In contrast, no significant effects of parental smoking were found on interleukin 4 production.

CONCLUSIONS. Interferon {gamma} responses of school-aged children are impacted by parental smoking.

Key Words: smoking • environmental tobacco smoke • ETS • interferon {gamma} • IFN-{gamma} • interleukin 4 • IL-4

Abbreviations: ETS—environmental tobacco smoke • Th—T-helper • IFN-{gamma}—interferon {gamma} • IL—interleukin • CRS—Children's Respiratory Study • LRI—lower respiratory illness • RSV—respiratory syncytial virus • OR—odds ratio • CI—confidence interval

Environmental tobacco smoke (ETS) has been consistently linked to negative health outcomes, especially among children.1–3 Among the negative effects of ETS exposure is an increased susceptibility to infections.4 It is now well established that children who are exposed to ETS are at increased risk for otitis media,5 respiratory syncytial virus bronchiolitis,6 bronchitis, and pneumonia.7

Despite this large body of evidence, the mechanisms by which ETS exposure during childhood may exert its deleterious effects remain unknown. One postulated mechanism is the impairment of the immune system function and/or development,8 which can, in turn, predispose ETS-exposed children to recurrent infections. In vitro studies have demonstrated depressive effects of cigarette smoke extracts on the production of several proinflammatory cytokines that are involved in the host defense against infections, including interferon {gamma} (IFN-{gamma}).9–11 IFN-{gamma} is a central cytokine in pathogen recognition, antiviral response, and activation of immune effector functions.12 The depressive effects of cigarette smoking on IFN-{gamma} have been confirmed in in vivo studies that have found decreased IFN-{gamma} levels13 and reduced numbers of IFN-{gamma}-secreting cells in serum and bronchoalveolar lavage fluid, respectively, from smokers. In contrast, other studies14,15 have failed to show significantly decreased production of IFN-{gamma} by polyclonally stimulated peripheral blood mononuclear cells of smokers, although in those studies production of T-helper (Th) 2–like cytokines, such as interleukin 4 (IL-4) and IL-13, was found to be indeed higher in smokers than nonsmokers, suggesting the existence of an altered Th1/Th2 balance associated with cigarette smoking.

Relatively few studies have assessed relations of exposure to maternal smoking in utero or exposure to parental smoking during childhood to cytokine production.16–20 At birth, serum levels of IFN-{gamma} were found to be reduced,16 and IL-13 production increased17 in newborns of mothers who smoked during pregnancy as compared with newborns of nonsmoking mothers. Similarly, IL-4 levels in the serum of school children18 and IL-13 levels in airway secretions of asthmatic children19 were reported to be increased in response to parental smoking. However, to date, no long-term birth cohort has attempted to study prospectively the effects of parental smoking on the child's cytokine production. Thus, it remains unknown whether cytokine production in childhood is altered by parental smoking in a dose-response fashion and whether these associations are independent of prenatal exposure to maternal smoking, given that children who are exposed to ETS during childhood are more likely to have also been exposed to maternal smoking in utero.

The aims of our study were to determine, in a population-based birth cohort, whether IFN-{gamma} and IL-4 production in school-aged children is altered in association with parental smoking, whether there is a dose-response relation with the level of exposure (defined in terms of parental pack-years assessed prospectively between birth and age 11 years), and whether these effects are independent of in utero exposure to maternal smoking.


   Methods
TOP
 ABSTRACT
 Methods
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Study Population and Cigarette Smoke Exposure
Between 1980 and 1984, 1246 healthy infants were enrolled at birth in the Tucson Children's Respiratory Study (CRS), a prospective population-based study of respiratory illness. Their parents were enrolled in a large health maintenance organization. The population consisted primarily of non-Hispanic white and Hispanic subjects, reflecting the general Tucson population. Detailed information on the design and enrollment process of this study has been published previously.21 The prospective schedule of evaluations and examinations that were used for the present study is shown in Table 1.


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  		TABLE 1 Prospective Schedule of Evaluations and Examinations That Children Included in the Present Study Completed During the CRS

 
Standardized questionnaires were completed by the parents at enrollment immediately after the child's birth and afterward. Information on parental smoking was collected at enrollment and when the child was, on average, 1.3 months (SD: 2.7 months); 5.3 years (SD: 1.1 years); 8.6 years (SD: 0.7 years); and 10.7 years (SD: 0.5 years) old. In the present study, parents were defined as smokers if they reported current smoking at enrollment or on any of the other follow-up questionnaires. If the mother reported either smoking regularly at enrollment or having smoked cigarettes while she was pregnant in the follow-up questionnaire, she was considered to have smoked in pregnancy.22 Pack-years of cigarettes smoked by each parent between child's birth and 11 years were computed on the basis of the reported number of cigarettes smoked daily at each parental questionnaire (area under the curve analysis). Parents with missing data at any of these time points were assigned a value of 0 for that time point. Pack-year values >0 were divided at the median into "low" and "high" groups for maternal pack-years (median: 3.73 pack-years), paternal pack-years (4.06 pack-years), and parental pack-years, that is, the sum of pack-years for both parents (4.96 pack-years). Children with one nonsmoking parent and missing smoking information for the other parent were excluded from analyses on combined parental smoking.

Cytokine Production
Peripheral blood samples were obtained from the children at age 11 years. Peripheral blood mononuclear cells were isolated by standard density-gradient centrifugation. Cells were stimulated at a concentration of 2 x 106 cells per mL with 10 µg/mL of concanavalin A and 10 ng/mL of phorbol 12-myristate 13-acetate (both from Sigma-Aldrich, St Louis, MO) and cultured for 18 to 24 hours. Supernatants were harvested and stored at –70°C and were later assayed for IFN-{gamma} and IL-4 production by using commercially available ELISA kits (Genzyme, Cambridge, MA).

Other Covariates
The ethnicity of each child was determined on the basis of parental ethnicity as self-reported by both mother and father in the enrollment questionnaire. Children were classified as having both parents non-Hispanic white, 1 Hispanic and 1 non-Hispanic white parent, both Hispanic parents, or other.

Wheezing status for each child was determined at age 11 years from parental report. Children were categorized as "never wheezers" (those with a negative report of ever wheezing), "inactive wheezers" (those who did not wheeze during the past year but had a previous history of wheezing), and "active wheezers" (those who wheezed during the past year). In addition, consistent with our previous report,23 4 phenotypes of preschool-aged wheeze were defined on the basis of the presence of physician-diagnosed wheezing lower respiratory illness (LRI) in the first 3 years of life and the presence of parent-reported wheeze during the past year for the child at age 6 years: no wheeze from birth to 6 years of age (never wheeze), wheezing LRI before age 3 years only (transient early wheeze), wheeze at 6 years of age only (late-onset wheeze), and wheezing LRI before age 3 years and wheeze at age 6 years (persistent wheeze).

Nasopharyngeal-throat swabs were obtained for viral culture from children at the time of every LRI from birth until age 3 years. Children were considered to have a history of respiratory syncytial virus (RSV) illness if viral culture or immunofluoroscopy assessment indicated the presence of RSV during any LRI.24

At age 11 years, children were skin-prick tested for sensitivity to 6 common aeroallergens (Alternaria alternata, careless weed, Bermuda grass, mulberry tree, olive tree, and mesquite tree). Tests were read after 20 minutes, and the size of the wheal elicited by each allergen was recorded as the longest diameter plus the widest perpendicular diameter (in millimeters). Wheal sizes of ≥3 mm, after subtracting the negative control, were considered positive results. Children were classified as skin-prick-test–positive if they had a positive response to ≥1 of the 6 aeroallergens. The study was approved by the human subjects committee at the University of Arizona.

Statistical Analysis
Because 23.4% of the IFN-{gamma} values at age 11 years were undetectable (≤25 pg/mL), the values were categorized into quartiles (low, medium-low, medium-high, and high IFN-{gamma} production). Approximately 66% of the IL-4 values at age 11 years were undetectable (≤12 pg/mL); hence, these values were categorized as undetectable or detectable.

Ordinal logistic regression was used to assess relationships between smoking exposures (independent variable) and IFN-{gamma} production (dependent variable). In ordinal logistic regression models, quartiles of IFN-{gamma} production were coded in reverse order (from high to low) to obtain odds ratios (ORs) associated with risk of reduced IFN-{gamma} production. Logistic regression was used to assess relationships between smoking exposures and IL-4 production.


   RESULTS
TOP
 ABSTRACT
 Methods
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Of the original 1246 enrolled children, a subgroup of 512 had data available for parental smoking and cytokine production at age 11 years (mean age at time of blood collection ± SD: 10.9 ± 0.7 years). Table 2 summarizes characteristics of children included and excluded from the current analysis. The 512 children included in the present analysis were more likely to have ≥1 Hispanic parent than were the 734 excluded children (29.2% vs 19.7%, respectively). No significant differences were found between the 2 groups in terms of gender, wheeze at age 11 years, skin-prick test results, and history of RSV infection.


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  		TABLE 2 Characteristics of CRS Participants Included and Excluded From the Current Study

 
Maternal smoking was reported for 33% and paternal smoking for 47% of the children included in this analysis. Overall, 57% of the children had ≥1 smoking parent. In Fig 1, the proportions of maternal, paternal, and parental smoking are compared among children in the 4 quartiles of IFN-{gamma} production. The proportion of children with parents who ever smoked between the prenatal period and year 11 decreased significantly across the IFN-{gamma} quartiles, suggesting suppressive effects of parental smoking on the child's IFN-{gamma} production. In contrast, no significant effects of parental smoking were found on IL-4 production (Fig 2).


Figure 1
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  		FIGURE 1 Proportions of maternal, paternal, and parental smoking (A, n = 477; B, n = 445; C, n = 471) among children in the 4 quartiles of IFN-{gamma} production at age 11 years. Error bars indicate 95% CIs, and P values refer to tests for trend.

 

Figure 2
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  		FIGURE 2 Proportions of maternal, paternal, and parental smoking (A, n = 463; B, n = 432; C, n = 455) among children with detectable and undetectable IL-4 production at age 11 years. Error bars indicate 95% CIs. NS indicates not significant.

 
The proportion of children who were in either of the 2 lowest IFN-{gamma} quartiles (ie, who had IFN-{gamma} values below the median) was very similar among children with only the mother smoking (53%), children with only the father smoking (53%), and children with both parents smoking (56%). Therefore, the overall parental smoking variable (either parent smoked) was used in the final ordinal logistic regression model shown in Table 3. After adjusting for covariates, parental smoking remained significantly associated with decreased IFN-{gamma} production in the child (adjusted OR: 1.61 [95% confidence interval (CI): 1.14–2.25]). Among the other clinical covariates, active wheezing was significantly associated with decreased IFN-{gamma} production, whereas having positive skin-prick test results did not reach statistical significance. When the same model was tested after replacing wheeze at age 11 years with the preschool wheeze phenotypes through age 6 years among the covariates, the adjusted OR for decreased IFN-{gamma} production associated with parental smoking did not change notably (OR: 1.59 [95% CI: 1.13–2.24]). In addition, maternal, paternal, and parental pack-years showed significant inverse dose-response relationships with IFN-{gamma} production in the child (Table 4).


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  		TABLE 3 Ordinal Logistic Regression Model for Predicting Decreased IFN-{gamma} Production at Age 11 Years (N = 471)

 

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  		TABLE 4 ORs for Predicting Decreased IFN-{gamma} Production at Age 11 Years Associated With Exposure to Different Levels of Parental Pack-Years as Assessed Between Child's Birth and 11 Years

 
To separate the effects of maternal smoking during pregnancy from those of maternal smoking after pregnancy, smoking mothers were classified as "continued smoking mothers" if they smoked both during pregnancy and after the child's birth (n = 94) and as "postnatal smoking mothers" if they smoked only after the child's birth but not during pregnancy (n = 60). Five mothers who smoked during pregnancy but not after the child's birth were excluded from subsequent analyses because of the small sample size of this group. As compared with children of mothers who never smoked, only children of continued-smoking mothers were at increased risk for having decreased IFN-{gamma} production at age 11 years (OR: 1.65 [95% CI: 1.09–2.50]). The corresponding OR for children of mothers who smoked postnatally only was 1.12 (95% CI: 0.68–1.84). However, continued-smoking mothers also had much higher pack-year values than did postnatal-smoking mothers (geometric means: 4.5 vs 1.2 pack-years, respectively; P < .0001), making it impossible to determine whether the increased risk among children of continued-smoking mothers was because of in utero exposure to ETS or to exposure to heavier maternal smoking during childhood.

However, after selecting for children of mothers who did not smoke during pregnancy, both paternal and parental pack-years remained significantly and inversely associated with IFN-{gamma} production in the child (P for test for trend: 0.019 and 0.012, respectively), and the magnitude of these associations, as assessed by the corresponding ORs, did not change appreciably as compared with the entire study population (Table 5). These findings suggest that the dose-response relationships described above are associated with exposures that take place after the child's birth.


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  		TABLE 5 ORs for Predicting Decreased IFN-{gamma} Production at Age 11 Years Associated With Exposure to Different Levels of Parental Pack-Years, as Assessed Between Child's Birth and 11 Years, Among Children of Mothers Who Did Not Smoke During Pregnancy

 

   DISCUSSION
TOP
 ABSTRACT
 Methods
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
In this study, we found that children of parents who smoke are more likely to have reduced IFN-{gamma} production at 11 years of age. The association between parental smoking and reduced IFN-{gamma} production of the child was independent of potential confounders, was consistent with a dose-response relationship (ie, the odds for having low IFN-{gamma} production increased across increasing parental pack-year categories), and remained significant after selecting for children of mothers who did not smoke during pregnancy. In contrast, no significant effects of ETS exposure on IL-4 production were found.

Parental smoking remains a common exposure and health hazard for children in the United States. In this study, we found that 57% of the children had either 1 or both parents who smoked at some point during their first 11 years of life. These data are not surprising when considering that, in the Third National Health and Nutrition Examination Survey (which was initiated in 1988), 38% of children 2 months through 5 years of age had current ETS exposure in the household, and 24% had been exposed to maternal smoking during pregnancy.25

The evidence for negative health outcomes associated with ETS exposure in children is well established1–3 and points out the public health importance associated with this exposure. Direct effects of secondhand smoking on the maturation of the immune system have been postulated as potential mechanisms for some of these ETS-related health outcomes, especially for the increased susceptibility to infections that is reported among children exposed to parental smoking.4 Our findings suggest that exposure to parental smoking is associated with depressive effects on IFN-{gamma} but not IL-4 production, and it may, thus, favor a predominance of Th2- versus Th1-type immune responses in childhood. Previous studies have shown that cigarette smoke extracts inhibit IFN-{gamma} production by peripheral blood mononuclear cells9 and that active smoking is associated with increased production of Th2-related cytokines.14,15 In addition, although maternal smoking during pregnancy has been shown to reduce both IFN-{gamma} and IL-4 serum levels at birth, children with asthma whose parents smoked ≥10 cigarettes per day were found recently to have highly increased IL-13 levels in airway secretions as compared with unexposed case and control subjects.19 Taken together, this evidence suggests that ETS exposure may inhibit immune responses involved in defense against infectious agents and favor a Th2 polarization of the immune system among exposed children. Consistent with this scenario, we have previously found IFN-{gamma} production to be inversely associated with risk of wheezing in infancy26 and common colds in childhood27 in 2 distinct birth cohorts. Also, in the present study, decreased IFN-{gamma} production at age 11 years was significantly associated with concurrent active wheezing, a respiratory phenotype that was linked previously to maternal smoking in this same cohort, although only in the first 3 years of life.22 However, it remains to be determined whether decreased IFN-{gamma} production is part of the causal pathway of ETS exposure to increased susceptibility to infections in children and to what extent these relations are age dependent.

The prospective nature of the CRS cohort allowed us to establish the existence of a dose-response relationship between cumulative parental pack-years and impairment of the child's IFN-{gamma} responses, an essential criterion for causality in epidemiologic studies. In addition, the availability of longitudinal information on parental smoking both during and after pregnancy made it possible to study to what extent the effects of postnatal ETS exposure on immune responses are independent of in utero exposure to maternal smoking. Although our study confirms the deleterious effects of prenatal exposure to maternal smoking, it also indicates independent effects of postnatal ETS exposure, because a dose-response relation of both paternal and parental smoking to IFN-{gamma} production was evident among children of mothers who did not smoke during pregnancy.

Cytokine data were available for 512 of the 1246 CRS participants, indicating the potential for selection bias in our study. However, the only significant difference between children included and excluded from the present analysis was that the former were more likely to have ≥1 Hispanic parent. No significant differences were found for other demographic and clinical characteristics, suggesting that the study sample was representative of the general population.


   CONCLUSION
TOP
 ABSTRACT
 Methods
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Our findings from a longitudinal population-based birth cohort suggest that parental smoking negatively impacts IFN-{gamma} responses of school-aged children.


   ACKNOWLEDGMENTS
 
This work was supported by National Heart Lung and Blood Institute grants HL14136 and HL-56177. Dr Guerra is the recipient of a Parker B. Francis Fellowship.

We thank Bruce Saul for data management and Marilyn Lindell and Lydia de la Ossa for data collection and participant follow-up.


   FOOTNOTES
 
Accepted Dec 12, 2007.

Address correspondence to Stefano Guerra, MD, PhD, Arizona Respiratory Center, University of Arizona, 1501 N Campbell Ave, PO Box 245030, Tucson, AZ 85724-5030. E-mail: sguerra{at}arc.arizona.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

ETS is associated with negative lung health outcomes in children, including increased susceptibility to infections. In vitro studies have demonstrated depressive effects of cigarette smoke extracts on the production of several cytokines involved in the defense against infectious agents, including IFN-{gamma}.

 

What This Study Adds

In this population-based study, we found dose-response relationships between parental cumulative pack-years and the risk of impaired IFN-{gamma} responses in the child, which were independent of in utero exposure to maternal smoking.

 


   REFERENCES
TOP
 ABSTRACT
 Methods
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics




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