Protein tyrosine phosphatases regulate asthma development in a murine asthma model.
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.
Pouliot
Philippe
P
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
Camateros
Pierre
P
Radzioch
Danuta
D
Lambrecht
Bart N
BN
Olivier
Martin
M
D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D045744:Cell Line, Tumor; D003888:Desensitization, Immunologic; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000097:blood; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000008:administration & dosage; D010618:Phenanthrolines / Q000008:administration & dosage; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D018417:Th1 Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D000485:Allergens; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D010618:Phenanthrolines; D007073:Immunoglobulin E; C102120:bisperoxo(1,10-phenanthroline)oxovanadate(1-); D007371:Interferon-gamma; D017027:Protein Tyrosine Phosphatases