Glutathione Transferase P1 An Endogenous Inhibitor of Allergic Responses in a Mouse Model of Asthma

Jiansheng Zhou, C. Roland Wolf, Colin J. Henderson, Yeping Cai, Philip G. Board, Paul S. Foster, Dianne C. Webb

    Research output: Contribution to journalArticlepeer-review

    18 Citations (Scopus)

    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 (INK) 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-tun 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.

    Original languageEnglish
    Pages (from-to)1202-1210
    Number of pages9
    JournalAmerican Journal of Respiratory and Critical Care Medicine
    Volume178
    Issue number12
    DOIs
    Publication statusPublished - 15 Dec 2008

    Keywords

    • asthma
    • oxidative stress
    • Th2 cytokines
    • JNK
    • N-TERMINAL KINASE
    • S-TRANSFERASE
    • AIRWAY INFLAMMATION
    • OXIDATIVE STRESS
    • 1-CYS PEROXIREDOXIN
    • IL-5 TRANSCRIPTION
    • CHILDHOOD ASTHMA
    • RISK-FACTORS
    • HUMAN LUNG
    • JUN

    Cite this