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Am J Respir Crit Care Med. 2008 Dec 15;178(12):1202-10. doi: 10.1164/rccm.200801-178OC. Epub 2008 Sep 11.

Glutathione transferase P1: an endogenous inhibitor of allergic responses in a mouse model of asthma.

Author information

1
Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.

Abstract

RATIONALE:

Although epidemiological studies have linked asthma susceptibility and severity to polymorphisms in human glutathione transferase Pi (GSTP) 1, there is no direct evidence for a functional involvement of GSTP1 in processes that are pathognomic of asthma.

OBJECTIVES:

To examine the role of GSTP1 in modulating the development of allergic airways disease.

METHODS:

Allergic airways disease was induced in wild-type (WT) and Gstp-null mice employing both acute and chronic models. Eosinophilia, goblet cells, and remodeling were quantified by histological assessment; respiratory function was determined using invasive methods. ELISA was used to evaluate Th2 cytokines, eotaxin, and phospho-c-Jun. Gstp1/2 expression was quantified by reverse transcriptase-polymerase chain reaction.

MEASUREMENTS AND MAIN RESULTS:

Compared with allergic WT mice, eosinophilia, goblet cell hyperplasia, airway remodeling, lung resistance, and IL-5 were enhanced in allergic Gstp-null mice. However, the protective efficacy of GSTP1 was mouse-strain dependent, and associated with inherent variation in expression of Gstp1. Although elevated levels of phospho-c-Jun were detected in Gstp-null mice, treatment of WT mice with a GSTP/c-Jun N-terminal kinase (JNK) inhibitory peptide enhanced phospho-c-Jun and significantly attenuated allergic responses.

CONCLUSIONS:

GSTP1 attenuates the severity of allergic airways disease. However, the efficacy of GSTP1 correlated with mouse strain-dependent variation in Gstp1 expression. Although GSTP1 attenuated c-Jun phosphorylation, treatment with a GSTP/JNK inhibitory peptide revealed an inverse relationship between c-Jun phosphorylation and allergic responses, indicating that the mechanism by which GSTP attenuates allergic responses is not dependent on the JNK/c-Jun axis. Our data, together with epidemiological evidence, suggest variation in expression and/or function of this protein is an important determinant in asthma pathophysiology.

PMID:
18787219
DOI:
10.1164/rccm.200801-178OC
[Indexed for MEDLINE]

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