A critical role for Pin1 in allergic pulmonary eosinophilia in rats

Background: Infiltration, accumulation, and degranulation of eosinophils in the lung are hallmarks of active allergic asthma. The pulmonary response to inhaled allergen triggers the secretion of eosinophil chemoattractants and antiapoptotic cytokines, including GM-CSF, IL-3, IL-4, IL-5, and eotaxin, among others. We recently showed that in vitro pint regulated eosinophil production of and response to GM-CSF. Objective: We sought to determine the effect of Pint inhibition on pulmonary eosinophilia after allergen challenge. Methods: The Pint inhibitorjuglone (5-bydroxy-1,4-naphthoquinone) was administered to allergen-sensitized and allergen-challenged Brown Norway rats. Bronchoalveolar lavage fluid and lungs were assessed for inflammation, cytokine expression, and Pin1 activity. Results: Juglone-treated rats showed a dramatic reduction (approximately 75%) in bronchoalveolar lavage fluid and pulmonary eosinophilia but no change in lymphocyte, monocyte/macrophage, or neutrophil numbers. GM-CSF and IL-5 expression were also significantly reduced, whereas Pin1-independent cytokines, such as eotaxin or IL-4, as well as housekeeping mRNAs and proteins, including actin, were unaffected by juglone. The eosinophils present in the lung in juglone-treated rats showed significantly greater apoptosis. Conclusion: These data suggest that in vivo Pint blockade attenuates GM-CSF and IL-5 production and can selectively reduce eosinophilic allergic inflammation. Clinical implications: Eosinophils can be selectively reduced by Pint blockade, despite allergen challenge.