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* Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada;
Centre for the Study of Host Resistance, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; and
Department of Respiratory Diseases, University Hospital Ghent, Ghent, Belgium
Allergic asthma is a chronic inflammatory disease characterized by Th2-type inflammation. Although the cellular interactions are now well studied, the intracellular signaling involved in asthma development is still a developing field. Protein tyrosine kinases are one focus of such research and their inhibition shows improvement of asthmatic features. Interestingly, very little attention was given to protein tyrosine phosphatases (PTPs), the counterparts to protein tyrosine kinases, in the development of asthma. Previous studies from our laboratory showed that pharmacological inhibition of PTPs induced a transient Th1 response in the spleen. Therefore, we hypothesized that modulation of PTPs could influence asthma development. To assess PTP functions, we used the PTP inhibitor bis-peroxovanadium bpV(phen) in a murine model of asthma during either allergen sensitization or challenge. Inhibition of PTPs during allergen sensitization resulted in the reduction of key features of allergic asthma: serum IgE levels, lung tissue inflammation, eosinophilia, and airway hyperresponsiveness. Of utmost interest, PTP inhibition at allergen challenge resulted in a very similar improvement of asthmatic features. Of further importance, we observed that bpV(phen) treatment modulated cytokine expression in the spleen and, more specifically, favored Th1 cytokines while inhibiting Th2 cytokines. Collectively, we show for the first time that intact activity of PTPs is required for a complete induction of asthma in a mouse model. This clearly suggests that PTPs have a pivotal regulatory role in the development of asthmatic diseases, which opens the possibility of new therapeutic avenues.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Funding was provided by the Canadian Institute of Health Research through an operating grant (to M.O.). P.P. is the recipient of a Canada Graduate Scholarships- Doctoral Award from the Canadian Institute of Health Research.
2 Address correspondence and reprint requests to Dr. Martin Olivier, Department of Microbiology and Immunology, McGill University, Lyman Duff Medical Building (Room 610), 3775 University Street, Montreal, Quebec, Canada H9S 3W6. E-mail address: martin.olivier{at}mcgill.ca
3 Abbreviations used in this paper: PTK, protein tyrosine kinase; PTP, protein tyrosine phosphatase; PTEN, phosphatase and tensin homolog; SHP, Src homology 2 domain-containing phosphatase; AHR, airway hyperresponsiveness; BALf, bronchoalveolar lavage fluid; DAPI, 4',6-diamidino-2-phenylindole; Penh, enhanced pause; pNPP, p-nitrophenyl phosphate; pV, bpV(phen); Sal, saline.
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