Mechanisms of allergy and clinical immunology
Cigarette smoke extract induces thymic stromal lymphopoietin expression, leading to TH2-type immune responses and airway inflammation

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Background

Both active and passive smoking are considered to be risk factors for asthma development. However, the precise mechanisms involved remain elusive. Recently, thymic stromal lymphopoietin (TSLP) has been shown to play a key role in the development of TH2-type allergic inflammation in patients with asthma.

Objective

The aim of this study was to investigate whether there was a causal relationship between cigarette smoke exposure and TSLP expression in the lung.

Methods

We examined the effects of repeated intranasal exposure of cigarette smoke extract (CSE) on TSLP mRNA and protein expression in the mouse lung by means of real-time PCR, Western blotting, and immunohistochemistry. We also examined the effects of intranasal exposure of CSE plus ovalbumin (OVA) on TH2-type immune responses and lung pathology.

Results

Repeated exposure of CSE induced TSLP mRNA and protein expression, which was inhibited by treatment with antioxidative N-acetylcysteine and by TNF-α receptor I deficiency. In addition, the intranasal exposure of CSE simultaneously with OVA induced OVA-specific TH2-type immune responses and airway inflammation, which were inhibited by the blockade of the TSLP activity.

Conclusion

CSE induced TSLP expression in the mouse lung in an oxidative stress–dependent and TNF-α receptor I–dependent manner, and when challenged simultaneously with an antigen, CSE promoted the development of airway inflammation in association with TH2-type immune responses.

Section snippets

Mice

Female inbred BALB/c mice, all approximately 6 weeks old, were obtained from Japan SLC (Tokyo, Japan). Homozygous wild-type C57BL/6J and TNF receptor 1–null B6.129-Tnfrsf1atm1Mak/J mice were purchased from The Jackson Laboratory (Bar Harbor, Me). The experimental protocols were approved by the Institutional Animal Care and Use Committee of the University of Yamanashi.

Preparation of CSE

CSE was prepared from a major cigarette brand in Japan (tar content, 10 mg), as previously described,10 and stored at −20°C until

CSE exposure induces TSLP expression in the mouse lung in an oxidative stress−dependent and TNF-α receptor I–dependent manner

To investigate whether a causal relationship exists between cigarette smoke exposure and TSLP expression in the lung, we first examined the effects of cigarette smoke exposure on TSLP expression in the mouse lung. BALB/c mice were intranasally exposed to CSE every day for a total of 7 days (days 0-6), and expression of TSLP mRNA and protein in the mouse lung was examined by means of real-time PCR, Western blotting, and immunohistochemistry. TSLP mRNA expression gradually increased in the lungs

Discussion

Exposure to cigarette smoke is strongly correlated with asthma severity and development,1, 2, 3, 4 although it remains a matter of debate whether there is a causal relationship between cigarette smoke exposure and asthma development. In this study we showed that exposure to CSE induced the expression of TSLP, a master switch of TH2-type allergic inflammation,6, 7, 8 in the mouse lung. Importantly, when simultaneously challenged with an innocuous antigen (OVA), CSE induced the development of

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Supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

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