title: 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-5.
abstract: 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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112, USA.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Oumouna
authors.forename: Oumouna
authors.initials: O
authors.lastname: Mustapha
authors.forename: Rahul
authors.initials: R
authors.lastname: Datta
authors.forename: Karine
authors.initials: K
authors.lastname: Oumouna-Benachour
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Chetan
authors.initials: C
authors.lastname: Hans
authors.forename: Kametra
authors.initials: K
authors.lastname: Matthews
authors.forename: Kenneth
authors.initials: K
authors.lastname: Fallon
authors.forename: Hamid
authors.initials: H
authors.lastname: Boulares
mesh_terms: D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D007073:Immunoglobulin E / Q000494:pharmacology; D007249:Inflammation / Q000201:enzymology / Q000276:immunology; D015848:Interleukin-5 / Q000378:metabolism* / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008168:Lung / Q000201:enzymology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000201:enzymology / Q000276:immunology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology*; D012130:Respiratory Hypersensitivity / Q000201:enzymology / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D016207:Cytokines; D015848:Interleukin-5; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013876:Thiophenes; C475227:thieno(2,3-c)isoquinolin-5-one; D007073:Immunoglobulin E; D010047:Ovalbumin; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases