title: PARP-1 deficiency blocks IL-5 expression through calpain-dependent degradation of STAT-6 in a murine asthma model.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, The Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Datta
authors.forename: A S
authors.initials: AS
authors.lastname: Naura
authors.forename: M
authors.initials: M
authors.lastname: Zerfaoui
authors.forename: Y
authors.initials: Y
authors.lastname: Errami
authors.forename: M
authors.initials: M
authors.lastname: Oumouna
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Ju
authors.forename: V P
authors.initials: VP
authors.lastname: Ronchi
authors.forename: A L
authors.initials: AL
authors.lastname: Haas
authors.forename: A H
authors.initials: AH
authors.lastname: Boulares
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology*; D002154:Calpain / Q000378:metabolism*; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000276:immunology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D012137:Respiratory System / Q000276:immunology / Q000503:physiopathology; D050800:STAT6 Transcription Factor / Q000378:metabolism*
chemical_list: D000485:Allergens; D015848:Interleukin-5; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002154:Calpain