T helper 2 (Th2) cells mediate immunity to parasites and promote allergic disease, while Th1 cells provide immunity to intracellular pathogens and initiate inflammation. IFN-??plays a major role in Th1 responses but inhibits the development of Th2 cells, while IL-4 promotes Th2 immunity and inhibits Th1 differentiation. The transcription factors Stat1 and Stat6 are the key signaling molecules for the cytokines IFN-?? and IL-4 respectively. We have identified a novel transcriptional cofactor, CoaSt6 (Collaborator of Stat6) that specifically enhances Stat6 but not Stat1 dependent transcription. Owing to the presence of macro domains and the PARP (poly ADP-ribose polymerase) catalytic domain, CoaSt6 belongs to the PARP family of proteins and is also called PARP-14. We have demonstrated that CoaSt6/PARP-14 contains PARP catalytic activity and preliminary data shows that inhibition of PARP activity with a pharmacological inhibitor targets IL-4 but not IFN-?? mediated gene induction. Furthermore, the differentiation of T helper cells into the Th2 phenotype is less efficient in the presence of PARP inhibitors. Our preliminary data also demonstrates that the intranasal administration of a PARP inhibitor to a mouse model of asthma reduces inflammation in the lung. The goal of this application is to elucidate the molecular mechanism by which CoaSt6/PARP-14 functions and to determine its role in T helper cell mediated immunity. The hypothesis for this proposal is that the macro and PARP domains of CoaSt6/PARP-14 employ a unique mechanism to regulate transcription and, the requirement of PARP activity for Th2 responses can be used as a therapeutic target for asthma. To address this hypothesis we will employ biochemical and molecular biological tools to define the mechanism by which CoaSt6/PARP-14 regulates transcription. Using a murine model we will determine the role of CoaSt6/PARP-14 in Th2 mediated allergic asthma. Further, we will investigate if inhibition of PARP activity in a mouse model of atopic airway hyperresponsiveness is able to alleviate this disease. Taken together, the proposed studies are aimed to understand the biological function of a novel transcriptional cofactor and will in fact test the feasibility of a therapy for allergic asthma.

Public Health Relevance

Current treatments for asthma include administration of glucocorticoids and leukotriene antagonists, which target the inflammatory response that cause the symptoms of asthma. It is known that T helper cells of the immune system play a critical role in the initiation and the progression of the asthmatic condition. The overall goal of this project is to develop a therapy for asthmatic patients by targeting their T helper cell responses that are responsible for the initiation of the asthmatic condition.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IMM-H (02))
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Noel, Patricia
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Mehrotra, Purvi; Krishnamurthy, Purna; Sun, Jie et al. (2015) Poly-ADP-ribosyl polymerase-14 promotes T helper 17 and follicular T helper development. Immunology 146:537-46
Krishnamurthy, Purna; Sherrill, Joseph D; Parashette, Kalyan et al. (2014) Correlation of increased PARP14 and CCL26 expression in biopsies from children with eosinophilic esophagitis. J Allergy Clin Immunol 133:577-80
Mehrotra, Purvi; Hollenbeck, Andrew; Riley, Jonathan P et al. (2013) Poly (ADP-ribose) polymerase 14 and its enzyme activity regulates T(H)2 differentiation and allergic airway disease. J Allergy Clin Immunol 131:521-31.e1-12
Riley, Jonathan P; Kulkarni, Aishwarya; Mehrotra, Purvi et al. (2013) PARP-14 binds specific DNA sequences to promote Th2 cell gene expression. PLoS One 8:e83127
Goswami, Ritobrata; Jabeen, Rukhsana; Yagi, Ryoji et al. (2012) STAT6-dependent regulation of Th9 development. J Immunol 188:968-75
Mehrotra, Purvi; Riley, Jonathan P; Patel, Ravi et al. (2011) PARP-14 functions as a transcriptional switch for Stat6-dependent gene activation. J Biol Chem 286:1767-76
Goenka, Shreevrat; Kaplan, Mark H (2011) Transcriptional regulation by STAT6. Immunol Res 50:87-96