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Poly(ADP-ribose) Polymerase-1 Inhibition Prevents Eosinophil Recruitment by Modulating Th2 Cytokines in a Murine Model of Allergic Airway Inflammation: A Potential Specific Effect on IL-5¹

Oumouna Mustapha^*, Rahul Datta^*, Karine Oumouna-Benachour^*, Yasuhiro Suzuki^*, Chetan Hans^*, Kametra Matthews^*, Kenneth Fallon and Hamid Boulares^2,3,*

^* Department of Pharmacology and Experimental Therapeutics, and Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA 70112

We recently used a murine model of allergic airway inflammation to show that poly(ADP-ribose) polymerase-1 (PARP-1) plays an important role in the pathogenesis of asthma-related lung inflammation. In this study, we show that PARP-1 inhibition, by a novel inhibitor (TIQ-A) or by gene deletion, prevented eosinophilic infiltration into the airways of OVA-challenged mice. Such impairment of eosinophil recruitment appeared to take place after IgE production. OVA challenge of wild-type mice resulted in a significant increase in IL-4, IL-5, IL-10, IL-13, and GM-CSF secretions. Although IL-4 production was moderately affected in OVA-challenged PARP-1^–/– mice, the production of IL-5, IL-10, IL-13, and GM-CSF was completely inhibited in ex vivo OVA-challenged lung cells derived from these animals. A single TIQ-A injection before OVA challenge in wild-type mice mimicked the latter effects. The marked effect PARP-1 inhibition exerted on mucus production corroborated the effects observed on the Th2 response. Although PARP-1 inhibition by gene knockout increased the production of the Th1 cytokines IL-2 and IL-12, the inhibition by TIQ-A exerted no effect on these two cytokines. The failure of lung cells derived from OVA-challenged PARP-1^–/– mice to synthesize GM-CSF, a key cytokine in eosinophil recruitment, was reestablished by replenishment of IL-5. Furthermore, intranasal administration of IL-5 restored the impairment of eosinophil recruitment and mucus production in OVA-challenged PARP-1^–/– mice. The replenishment of either IL-4 or IgE, however, did not result in such phenotype reversals. Altogether, these results suggest that PARP-1 plays a critical role in eosinophil recruitment by specifically regulating the cascade leading to IL-5 production.

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 This work was supported in part by Grants HL072889 and 1P20RR18766 (with overall principal investigator Dr. S. Lanier) from the National Institutes of Health and funds from Louisiana State University Health Sciences Center, New Orleans, LA (to H.B.).

² Current address: Ochsner Clinic Foundation, 1516 Jefferson Highway, Old Research Building Room 233, Jefferson, LA 70121.

³ Address correspondence and reprint requests to Dr. Hamid Boulares, Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112. E-mail address: hboulr{at}lsuhsc.edu

⁴ Abbreviations used in this paper: PARP-1, poly(ADP-ribose) polymerase; TIQ-A, thieno[2,3-c]isoquinolin-5-one; iNOS, inducible NO synthase; PAS, periodic acid-Schiff; BAL, bronchoalveolar lavage.

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