PARP-1 deficiency blocks IL-5 expression through calpain-dependent degradation of STAT-6 in a murine asthma model
R Datta1, A S Naura, M Zerfaoui
1Department of Pharmacology, The Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
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.
Insights
Poly(ADP-ribose)polymerase-1 (PARP-1) regulates allergen-induced IL-5 production by maintaining STAT-6 protein integrity. PARP-1 inhibition reduces eosinophilia by decreasing IL-5 expression through STAT-6 degradation.
Area of Science:
- Immunology
- Molecular Biology
- Inflammation Research
Background:
- Poly(ADP-ribose)polymerase-1 (PARP-1) involvement in allergen-induced airway eosinophilia, particularly IL-5 production, was previously suggested.
- IL-5 replenishment reversed eosinophilia in PARP-1 knockout mice, unlike IL-4 or IgE, indicating a specific PARP-1/IL-5 regulatory link.
Purpose of the Study:
- To elucidate the mechanism of PARP-1 in regulating IL-5 production.
- To determine how PARP-1 inhibition mitigates allergen-induced eosinophilia.
Main Methods:
- Utilized a murine model of allergic airway inflammation.
- Employed primary splenocytes for mechanistic studies.
Main Results:
- PARP-1 knockout reduced IL-5 at the mRNA level post-IL-4 receptor activation, without affecting JAK1/JAK3 activation.
- Signal transducer and activator of transcription-6 (STAT-6) protein was downregulated in PARP-1 knockout mice, dependent on allergen stimulation and PARP-1 activity.
- STAT-6 degradation correlated with reduced GATA-binding protein-3 and IL-5 promoter binding, and was mediated by calpain, not proteasomes.
Conclusions:
- Established a novel role for PARP-1 in controlling IL-5 expression during allergic inflammation.
- Explained the mechanism underlying PARP-1 inhibition-induced reduction of IL-5 and eosinophilia.
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