BACKGROUND: IL-4 and signal transducer and activator of transcription 6 (STAT6) play an important role in the progression of allergic airway disease (AAD) or asthma. IL-4 and STAT6 mediate T(H)2 responses in T cells and immunoglobulin class-switching to IgE in B cells. Both T(H)2 responses and IgE promote the asthmatic condition. We have previously demonstrated that poly (ADP-ribose) polymerase (PARP) 14, a member of the PARP family of proteins, regulates the transcription function of STAT6. However, the role of PARP-14 in AAD is not known. OBJECTIVE: Here we investigate the role of PARP-14 and the enzyme activity associated with it in a model of AAD dependent on airway hyperresponsiveness and lung inflammation. We also elucidate the mechanism by which PARP-14 regulates AAD. METHODS: The role of PARP-14 and its enzyme activity in AAD and T(H)2 differentiation were examined by using a murine model of AAD and in vitro T(H) cell differentiation. RESULTS: PARP-14-deficient animals show reduced lung pathology and IgE levels when compared with control animals. Treating mice with a pharmacologic inhibitor for PARP activity reduced the severity of airway hyperresponsiveness and lung inflammation. Mechanistically, our data indicate that PARP-14 and its enzyme activity aid in the differentiation of T cells toward a T(H)2 phenotype by regulating the binding of STAT6 to the Gata3 promoter. CONCLUSION: PARP-14 and the catalytic activity associated with it promote T(H)2 differentiation and AAD in a murine model, and targeting PARP-14 might be a potential new therapy for allergic asthma.
BACKGROUND:IL-4 and signal transducer and activator of transcription 6 (STAT6) play an important role in the progression of allergic airway disease (AAD) or asthma. IL-4 and STAT6 mediate T(H)2 responses in T cells and immunoglobulin class-switching to IgE in B cells. Both T(H)2 responses and IgE promote the asthmatic condition. We have previously demonstrated that poly (ADP-ribose) polymerase (PARP) 14, a member of the PARP family of proteins, regulates the transcription function of STAT6. However, the role of PARP-14 in AAD is not known. OBJECTIVE: Here we investigate the role of PARP-14 and the enzyme activity associated with it in a model of AAD dependent on airway hyperresponsiveness and lung inflammation. We also elucidate the mechanism by which PARP-14 regulates AAD. METHODS: The role of PARP-14 and its enzyme activity in AAD and T(H)2 differentiation were examined by using a murine model of AAD and in vitro T(H) cell differentiation. RESULTS:PARP-14-deficient animals show reduced lung pathology and IgE levels when compared with control animals. Treating mice with a pharmacologic inhibitor for PARP activity reduced the severity of airway hyperresponsiveness and lung inflammation. Mechanistically, our data indicate that PARP-14 and its enzyme activity aid in the differentiation of T cells toward a T(H)2 phenotype by regulating the binding of STAT6 to the Gata3 promoter. CONCLUSION:PARP-14 and the catalytic activity associated with it promote T(H)2 differentiation and AAD in a murine model, and targeting PARP-14 might be a potential new therapy for allergic asthma.
Authors: Jinfang Zhu; Liying Guo; Booki Min; Cynthia J Watson; Jane Hu-Li; Howard A Young; Philip N Tsichlis; William E Paul Journal: Immunity Date: 2002-05 Impact factor: 31.745
Authors: K Shimoda; J van Deursen; M Y Sangster; S R Sarawar; R T Carson; R A Tripp; C Chu; F W Quelle; T Nosaka; D A Vignali; P C Doherty; G Grosveld; W E Paul; J N Ihle Journal: Nature Date: 1996-04-18 Impact factor: 49.962
Authors: K Takeda; T Tanaka; W Shi; M Matsumoto; M Minami; S Kashiwamura; K Nakanishi; N Yoshida; T Kishimoto; S Akira Journal: Nature Date: 1996-04-18 Impact factor: 49.962
Authors: Sung Hoon Cho; Ariel Raybuck; Mei Wei; John Erickson; Ki Taek Nam; Reagan G Cox; Alyssa Trochtenberg; James W Thomas; John Williams; Mark Boothby Journal: J Immunol Date: 2013-08-16 Impact factor: 5.422
Authors: Purna Krishnamurthy; Joseph D Sherrill; Kalyan Parashette; Shreevrat Goenka; Marc E Rothenberg; Sandeep Gupta; Mark H Kaplan Journal: J Allergy Clin Immunol Date: 2013-11-12 Impact factor: 10.793