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 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 IgE 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. 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 dowregulation of STAT-6 coincided with mRNA and protein reduction of GATA-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.

PARP inhibitor, olaparib ameliorates acute lung and kidney injury upon intratracheal administration of LPS in mice

“…In our study, we found that LPS induced significant neutrophil infiltration in lungs which is in agreement with earlier reports [61][62][63]. Previously, we have shown that PARP inhibition blocks the lung inflammation in the context of ALI and asthma [29,31,32,[64][65][66][67]. Pharmacological inhibition of PARP has been investigated in various experimental conditions of ALI or other organ(s) injury mediated by systemic exposure of LPS [31,32,[67][68][69][70].…”

Investigation of Poly (ADP-Ribose) Polymerase-1 Genetic Variants as a Possible Risk for Allergic Rhinitis

“…It is believed that this enzyme mediates inflammation through promotion of cell death by means of ATP depletion as well as transcription of inflammatory factors (Datta et al, 2011). Upon activation, PARP-1 catalyzes the formation of poly (ADP-ribose) chains by transferring (ADP-ribose) from NAD onto itself and nuclear acceptor proteins.…”

Role of poly(ADP‐ribose) polymerases in the regulation of inflammatory processes

“…Whereas the NFjB co-activator function of PARP-1 has been made responsible for the effects of PARP inhibitors in Th1 diseases (and this may also contribute to the pathology of Th2-mediated conditions), recently a novel mechanism has been described for asthma, a prototypical Th2-mediated disease. Datta et al [64] have demonstrated in a murine model of asthma that inhibition of eosinophil migration in PARP-1 À/À mice is controlled at a step downstream of IL-4 and upstream of IL-5. PARP-1 was found to stabilize STAT-6 protein (without affecting mRNA) in an allergen-stimulation dependent manner.…”