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Follistatin is a candidate endogenous negative regulator of activin A in experimental allergic asthma

Authors

  • C. L. Hardy,

    1. Department of Immunology, Monash University, Melbourne, Australia,
    2. Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Vic., Australia,
    3. CRC for Asthma, Sydney, Australia,
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  • A. E. O'Connor,

    1. Monash Institute of Medical Research, Monash University, Melbourne, Australia
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  • J. Yao,

    1. Department of Immunology, Monash University, Melbourne, Australia,
    2. Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Vic., Australia,
    3. CRC for Asthma, Sydney, Australia,
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  • K. Sebire,

    1. Monash Institute of Medical Research, Monash University, Melbourne, Australia
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  • D. M. De Kretser,

    1. Monash Institute of Medical Research, Monash University, Melbourne, Australia
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  • J. M. Rolland,

    1. Department of Immunology, Monash University, Melbourne, Australia,
    2. Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Vic., Australia,
    3. CRC for Asthma, Sydney, Australia,
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  • G. P. Anderson,

    1. Departments of Medicine and Pharmacology and CRC for Chronic Inflammatory Disease, University of Melbourne, Melbourne, Australia
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  • D. J. Phillips,

    1. Monash Institute of Medical Research, Monash University, Melbourne, Australia
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  • R. E. O'Hehir

    1. Department of Immunology, Monash University, Melbourne, Australia,
    2. Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Vic., Australia,
    3. CRC for Asthma, Sydney, Australia,
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Correspondence:
Dr Charles Hardy, Department of Immunology, Monash University, Commercial Road, Melbourne, Vic. 3004, Australia. Email: charles.hardy@med.monash.edu.au

Summary

Background Activin A is a member of the transforming growth factor-β superfamily which is directly implicated in airway structural change and inflammation in asthma. In vitro, the biological effects of activin A are neutralized by the soluble binding protein follistatin.

Objective To determine the potential of endogenous follistatin to suppress activin A in vivo by analysing their relative tissue and kinetic compartmentalization during the effector phase of subchronic Th2-driven mucosal inflammation in a murine model of allergic asthma.

Methods Eosinophilic mucosal inflammation was elicited by triggering Th2 recall responses by antigen challenge in ovalbumin-sensitized BALB/c mice. The kinetics and distribution of activin A and follistatin protein were assessed in lung tissue and bronchoalveolar lavage fluid and measured in relation to airway eosinophilia, goblet cell metaplasia and Th2 cytokine production in mediastinal lymph nodes.

Results Follistatin was released concurrently with activin A suggesting it acts as an endogenous regulator: peak BAL concentrations coincided with maximal airway eosinophilia, and frequency of IL-4, IL-5 and IL-13 producing cells in mediastinal lymph nodes but induction lagged behind the onset of inflammation. Follistatin and activin A immunoreactivity were lost in airway epithelial cells in parallel with goblet cell metaplasia. Exogenous follistatin inhibited the allergen-specific Th2 immune response in mediastinal lymph nodes and mucus production in the lung.

Conclusion Follistatin is preformed in the normal lung and released in concert with activin A suggesting it serves as an endogenous regulator. Disturbance of the fine balance between activin A and its endogenous inhibitor follistatin may be a determinant of the severity of allergic inflammation or tissue phenotypic shift in asthma.

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