Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Dec;69(12):1666-72.
doi: 10.1111/all.12506. Epub 2014 Oct 1.

Glutathione S-transferase M1 modulates allergen-induced NF-κB activation in asthmatic airway epithelium

V V Polosukhin  1 , I V Polosukhin, A Hoskins, W Han, R Abdolrasulnia, T S Blackwell, R Dworski
Affiliations

Glutathione S-transferase M1 modulates allergen-induced NF-κB activation in asthmatic airway epithelium

V V Polosukhin et al. Allergy. 2014 Dec.

Abstract

Background: Glutathione S-transferase M1 (GSTM1) is a phase II enzyme and regulator of inflammatory signaling in airway epithelial cells. We have found upregulation of neutrophilic airway inflammation in atopic asthmatics expressing GSTM1 gene (GSTM1+) compared to GSTM1null asthmatics. We hypothesized that GSTM1 modulates NF-κB activation in bronchial epithelium in atopic asthmatics. We determined regulation of allergen-induced NF-κB activation in bronchial epithelium by GSTM1 in human atopic asthmatics in vivo.

Methods: Endobronchial biopsies and bronchoalveolar lavage fluid samples were collected from 13 GSTM1+ and 12 GSTM1null human atopic asthmatics at baseline and 24 h after segmental allergen challenge. A quantitative analysis of NF-κB activation in airway epithelium was accomplished using a polyclonal antibody against the phosphorylated p65 component of NF-κB. Elastase-positive neutrophils in the bronchial wall were quantified.

Results: Postallergen neutrophilia in airway subepithelium and epithelial lining fluid was greater in GSTM1+ compared to GSTM1null asthmatics. Airway eosinophilia was similar in GSTM1+ and GSTM1null asthmatics. Allergen-provoked NF-κB induction in bronchial epithelium was significantly greater in GSTM1+ compared to GSTM1null asthmatics. Activation of NF-κB activation in airway epithelial cells correlated with interleukin-8 concentrations and absolute neutrophil numbers in bronchoalveolar lavage fluid in GSTM1+ but not GSTM1null asthmatics.

Conclusions: Allergen-induced neutrophilic airway inflammation in GSTM1+ asthmatics is associated with NF-κB activation in airway epithelial cells in vivo. These novel data provide a potential mechanism of the genomic link between GSTM1 polymorphism and airway neutrophilia in atopic asthma.

Keywords: GSTM1 polymorphism; NF-κB; airway epithelium; atopic asthma; neutrophilic airway inflammation.

PubMed Disclaimer

Conflict of interest statement

Disclosure of potential conflict of interest: The authors have declared that they have no potential conflict of interest or commercial associations as per journal policy.

Figures

Figure 1
Figure 1. The effect of GSTM1 genotype on bronchial wall neutrophils and eosinophils in atopic asthmatics in vivo
Exemplary airway biopsies stained with neutrophil elastase at baseline and after allergen challenge in GSTM1null (A–B) and GSTM1+ (C–D) asthmatics. Neutrophil (E) and eosinophil (F) counts in bronchial subepithelium at baseline (Baseline) and after allergen challenge (Allergen) in GSTM1null and GSTM1+ asthmatics.
Figure 2
Figure 2. The effect of GSTM1 genotype on neutrophils and eosinophils in BAL fluid in atopic asthmatics in vivo
Representative cytospine slides stained with hematoxylin and eosin at baseline and after allergen challenge in GSTM1null (A–B) and GSTM1+ (C–D) asthmatics. Absolute neutrophil (E) and eosinophil (F) counts in BAL fluid at baseline (Baseline) and after allergen challenge (Allergen) in GSTM1null and GSTM1+ asthmatics.
Figure 3
Figure 3. Expression of p65 in airway epithelial cells in atopic asthmatics with GSTM1null and GSTM1+ genotypes in vivo (x200)
Typical images of airway biopsies stained with an antibody against phosphorylated p65 (ser276) at baseline and after allergen challenge in GSTM1null (A–B) and GSTM1+ (C–D) asthmatics. E. Percentages of phospho-p65-positive airway epithelial cells at baseline (Baseline) and post allergen (Allergen) in GSTM1null and GSTM1+ asthmatics. F. Intensity of phospho-p65-specific fluorescent signal in GSTM1null and GSTM1+ asthmatics at baseline (Baseline) and after allergen challenge (Allergen).
Figure 4
Figure 4. Relationship between expression of p65 in airway epithelium and production of Il-8 in airway space after SAC in human atopic asthmatics in vivo
The post-allergen percentages of p65 positive bronchial cells detected in airway biopsies positively correlate with levels of IL-8 in BAL fluid (* Spearman r=0.8, p=0.001).
See this image and copyright information in PMC

References

    1. Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev Pharmacol Toxicol. 2005;45:51–88. - PubMed
    1. McCarroll SA, Hadnott TN, Perry GH, Sabeti PC, Zody MC, Barrett JC, et al. Common deletion polymorphisms in the human genoms. Nature Genetics. 2012;38:86–92. - PubMed
    1. Anttila S, Hirvonen A, Vainio H, Husgafvel-Pursiainen K, Hayes JD, Ketterer B. Immunohistochemical localization of glutathione S-transferases in the lung. Cancer Res. 1993;53:5643–8. - PubMed
    1. Cho S-G, Lee YH, Park H-S, Ryoo K, Kang KW, Park J, Eom S-J, et al. Glutathione S-Transferase Mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1. J Biol Chem. 2001;16:12749–55. - PubMed
    1. Dorion S, Lambert H, Landry J. Activation of the p38 signaling pathway by heat shock involves the dissociation of glutathione S-transferase Mu from Ask1. J Biol Chem. 2002;277:30792–7. - PubMed

Publication types

MeSH terms