T cell-derived Act1 is necessary for IL-25-mediated Th2 responses and allergic airway inflammation

Shadi Swaidani; Katarzyna Bulek; Zizhen Kang; Muhammet Fatih Gulen; Caini Liu; Weiguo Yin; Amina Abbadi; Mark Aronica; Xiaoxia Li

doi:10.4049/jimmunol.1002790

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T cell-derived Act1 is necessary for IL-25-mediated Th2 responses and allergic airway inflammation

Journal article

Peer reviewed

T cell-derived Act1 is necessary for IL-25-mediated Th2 responses and allergic airway inflammation

Shadi Swaidani, Katarzyna Bulek, Zizhen Kang, Muhammet Fatih Gulen, Caini Liu, Weiguo Yin, Amina Abbadi, Mark Aronica and Xiaoxia Li

The Journal of immunology (1950), Vol.187(6), pp.3155-3164

09/15/2011

DOI: 10.4049/jimmunol.1002790

PMCID: PMC3666175

PMID: 21856933

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Abstract

The cellular and molecular mechanisms driven by IL-25 and its cognate receptor IL-17RB necessary for the promotion of Th2-mediating pathogenic pulmonary inflammation remains to be defined. We have previously reported the critical role of the U-box-type E3 ubiquitin ligase Act1 (1) for the downstream signaling of the IL-17 cytokine family including the Th2-promoting cytokine IL-25 (IL-17E) (2). In this study, we report that IL-25-driven but not conventional IL-4-driven Th2 polarization and cytokine production is impaired in Act1-deficient T cells. Also, Act1 deficiency in the T cell compartment results in the abrogation of eosinophilic airway infiltration as well as airway hyperresponsiveness in mouse models of Ag-induced airway inflammation. The in vivo generation of Ag-specific Th2 cytokine-producing cells is defective in the absence of Act1 expression in T cells after OVA/aluminum hydroxide immunization. Notably, the production of OVA-specific IgG(1) but not IgG(2a) or IgE is also impaired. At the molecular level, we report that IL-25-mediated induction of Th2 master regulator GATA-3 and the transcription factor GFI-1 is attenuated in Act1-deficient T cells. Taken together, our findings indicate that Act1 expression in T cells is required for cellular and humoral Th2-mediated allergic responses and the development of airway hyperresponsiveness, in part, through Act1's function in IL-25-induced development of Th2 T cells.

Adaptor Proteins, Signal Transducing - immunology

Adaptor Proteins, Signal Transducing - metabolism

Animals

Bronchial Hyperreactivity - immunology

Bronchial Hyperreactivity - metabolism

Disease Models, Animal

Enzyme-Linked Immunosorbent Assay

Hypersensitivity - immunology

Hypersensitivity - metabolism

Immunohistochemistry

Interleukins - immunology

Interleukins - metabolism

Mice

Mice, Knockout

Mice, Transgenic

Pneumonia - immunology

Pneumonia - metabolism

Signal Transduction - immunology

Th2 Cells - immunology

Th2 Cells - metabolism

Details

Title: Subtitle: T cell-derived Act1 is necessary for IL-25-mediated Th2 responses and allergic airway inflammation
Creators: Shadi Swaidani - Cleveland Clinic
Katarzyna Bulek - Cleveland Clinic
Zizhen Kang - Cleveland Clinic
Muhammet Fatih Gulen - Cleveland Clinic
Caini Liu - Cleveland Clinic
Weiguo Yin - Cleveland Clinic
Amina Abbadi - Cleveland Clinic
Mark Aronica - Cleveland Clinic
Xiaoxia Li - Cleveland Clinic
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.187(6), pp.3155-3164
DOI: 10.4049/jimmunol.1002790
PMID: 21856933
PMCID: PMC3666175
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Grant note: P01 HL103453 / NHLBI NIH HHS P01 HL029582 / NHLBI NIH HHS
Language: English
Date published: 09/15/2011
Academic Unit: Pathology; Iowa Neuroscience Institute
Record Identifier: 9984201121302771

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