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PARP‐1 deficiency blocks IL‐5 expression through calpain‐dependent degradation of STAT‐6 in a murine asthma model
Author(s) -
Datta R.,
Naura A. S.,
Zerfaoui M.,
Errami Y.,
Oumouna M.,
Kim H.,
Ju J.,
Ronchi V. P.,
Haas A. L.,
Boulares A. H.
Publication year - 2011
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/j.1398-9995.2011.02549.x
Subject(s) - poly adp ribose polymerase , stat , parp inhibitor , stat protein , eosinophilia , immunology , stat6 , stat3 , biology , microbiology and biotechnology , cancer research , cytokine , interleukin 4 , signal transduction , polymerase , enzyme , biochemistry
To cite this article: Datta R, Naura AS, Zerfaoui M, Errami Y, Oumouna M, Kim H, Ju J, Ronchi VP, Haas AL, Boulares AH. PARP‐1 deficiency blocks IL‐5 expression through calpain‐dependent degradation of STAT‐6 in a murine asthma model. Allergy 2011; 66 : 853–861. Abstract Background: We recently showed that poly(ADP‐ribose)polymerase‐1 (PARP‐1) may play a role in allergen (ovalbumin)‐induced airway eosinophilia, potentially through a specific effect on IL‐5 production. We also reported that while IL‐5 replenishment promotes reversal of eosinophilia in lungs of PARP‐1 −/− mice, IL‐4 or Immunoglobulin E replenishment do not, suggesting a potentially significant regulatory relationship between PARP‐1 and IL‐5. Objective: To explore the mechanism by which PARP‐1 regulates IL‐5 production and to determine how PARP‐1 inhibition blocks allergen‐induced eosinophilia. Methods: This study was conducted using a murine model of allergic airway inflammation and primary splenocytes. Results: PARP‐1 knockout‐associated reduction in IL‐5 upon allergen exposure occurs at the mRNA level. Such an effect appears to take place after IL‐4 receptor activation as PARP‐1 inhibition exerted no effect on JAK1/JAK3 activation. Signal transducer and activator of transcription‐6 (STAT‐6) protein was severely downregulated in spleens of PARP‐1 −/− mice without any effect on mRNA levels, suggesting an effect on protein integrity rather than gene transcription. Interestingly, the degradation of STAT‐6 in PARP‐1 −/− mice required allergen stimulation. Additionally, PARP‐1 enzymatic activity appears to be required for STAT‐6 integrity. The downregulation of STAT‐6 coincided with mRNA and protein reduction of GATA‐binding protein‐3 and occupancy of its binding site on the IL‐5 gene promoter. IL‐4 was sufficient to induce STAT‐6 downregulation in both PARP‐1 −/− mice and isolated splenocytes. Such degradation may be mediated by calpain, but not by proteasomes. Conclusion: These results demonstrate a novel function of PARP‐1 in regulating IL‐5 expression during allergen‐induced inflammation and explain the underlying mechanism by which PARP‐1 inhibition results in IL‐5 reduction.