STAT6 and PARP Family Members in the Development of T Cell-dependent Allergic Inflammation

Allergic inflammation requires the orchestration of altered gene expression in the target tissue and in the infiltrating immune cells. The transcription factor STAT6 is critical in activating cytokine gene expression and cytokine signaling both in the immune cells and in target tissue cells including airway epithelia, keratinocytes and esophageal epithelial cells. STAT6 is activated by the cytokines IL-4 and IL-13 to mediate the pathogenesis of allergic disorders such as asthma, atopic dermatitis, food allergy and eosinophilic esophagitis (EoE). In this review, we summarize the role of STAT6 in allergic diseases, its interaction with the co-factor PARP14 and the molecular mechanisms by which STAT6 and PARP14 regulate gene transcription.

[1]  M. Kaplan,et al.  Poly‐ADP‐ribosyl polymerase‐14 promotes T helper 17 and follicular T helper development , 2015, Immunology.

[2]  A. Barski,et al.  Induction of Interleukin-9-Producing Mucosal Mast Cells Promotes Susceptibility to IgE-Mediated Experimental Food Allergy. , 2015, Immunity.

[3]  T. Chatila,et al.  Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. , 2015, Immunity.

[4]  S. Crotty T follicular helper cell differentiation, function, and roles in disease. , 2014, Immunity.

[5]  I. Matic,et al.  Family-wide analysis of poly(ADP-ribose) polymerase activity , 2014, Nature Communications.

[6]  M. Kaplan,et al.  STAT6-mediated keratitis and blepharitis: a novel murine model of ocular atopic dermatitis. , 2014, Investigative ophthalmology & visual science.

[7]  M. Kaplan,et al.  Correlation of increased PARP14 and CCL26 expression in biopsies from children with eosinophilic esophagitis. , 2014, The Journal of allergy and clinical immunology.

[8]  M. Kaplan,et al.  PARP-14 Binds Specific DNA Sequences to Promote Th2 Cell Gene Expression , 2013, PloS one.

[9]  W. Zwart,et al.  Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis , 2013, Mucosal Immunology.

[10]  M. Rosado,et al.  Beyond DNA repair, the immunological role of PARP‐1 and its siblings , 2013, Immunology.

[11]  R. Niranjan,et al.  Pathogenesis of allergen-induced eosinophilic esophagitis is independent of Interleukin (IL)-13 , 2013, Immunology and cell biology.

[12]  S. Goenka,et al.  Poly (ADP-ribose) polymerase 14 and its enzyme activity regulates T(H)2 differentiation and allergic airway disease. , 2013, The Journal of allergy and clinical immunology.

[13]  S. Spechler,et al.  Omeprazole Blocks STAT6 Binding to the Eotaxin-3 Promoter in Eosinophilic Esophagitis Cells , 2012, PloS one.

[14]  T. Chatila,et al.  Direct effects of IL-4 on mast cells drive their intestinal expansion and increase susceptibility to anaphylaxis in a murine model of food allergy , 2012, Mucosal Immunology.

[15]  D. Kemeny The role of the T follicular helper cells in allergic disease , 2012, Cellular and Molecular Immunology.

[16]  S. London,et al.  STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children. , 2012, The Journal of allergy and clinical immunology.

[17]  A. Haas,et al.  PARP‐1 deficiency blocks IL‐5 expression through calpain‐dependent degradation of STAT‐6 in a murine asthma model , 2011, Allergy.

[18]  T. Chatila,et al.  IgE-mediated systemic anaphylaxis and impaired tolerance to food antigens in mice with enhanced IL-4 receptor signaling. , 2011, The Journal of allergy and clinical immunology.

[19]  S. Goenka,et al.  PARP-14 Functions as a Transcriptional Switch for Stat6-dependent Gene Activation* , 2010, The Journal of Biological Chemistry.

[20]  V. Schreiber,et al.  Genetic ablation of PARP-1 protects against oxazolone-induced contact hypersensitivity by modulating oxidative stress. , 2010, The Journal of investigative dermatology.

[21]  M. Rosado,et al.  Increased Foxp3+ Regulatory T Cells in Poly(ADP-Ribose) Polymerase-1 Deficiency , 2010, The Journal of Immunology.

[22]  Lisa J. Martin,et al.  Coordinate Interaction between IL-13 and Epithelial Differentiation Cluster Genes in Eosinophilic Esophagitis , 2010, The Journal of Immunology.

[23]  Bernhard Lüscher,et al.  Toward a unified nomenclature for mammalian ADP-ribosyltransferases. , 2010, Trends in biochemical sciences.

[24]  M. Kaplan,et al.  IL-4 Regulates Skin Homeostasis and the Predisposition toward Allergic Skin Inflammation , 2010, The Journal of Immunology.

[25]  J. Alcorn,et al.  TH17 cells in asthma and COPD. , 2010, Annual review of physiology.

[26]  R. Lahesmaa,et al.  PARP-14, a member of the B aggressive lymphoma family, transduces survival signals in primary B cells. , 2009, Blood.

[27]  J. Schroeder,et al.  Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. , 2009, The Journal of investigative dermatology.

[28]  Y. Chiba,et al.  A novel STAT6 inhibitor AS1517499 ameliorates antigen-induced bronchial hypercontractility in mice. , 2009, American journal of respiratory cell and molecular biology.

[29]  Stephen J. Galli,et al.  The development of allergic inflammation , 2008, Nature.

[30]  A. Boulares,et al.  Post‐allergen challenge inhibition of poly(ADP‐ribose) polymerase harbors therapeutic potential for treatment of allergic airway inflammation , 2008, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[31]  J. Yélamos,et al.  Transcriptional regulation by Poly(ADP-ribose) polymerase-1 during T cell activation , 2008, BMC Genomics.

[32]  F. Finkelman,et al.  IL-9– and mast cell–mediated intestinal permeability predisposes to oral antigen hypersensitivity , 2008, The Journal of experimental medicine.

[33]  M. Kaplan,et al.  IL-4 Is a Critical Determinant in the Generation of Allergic Inflammation Initiated by a Constitutively Active Stat6 , 2008, The Journal of Immunology.

[34]  M. Boguniewicz,et al.  Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. , 2008, Clinical immunology.

[35]  Xiaoyong Yang,et al.  Regulation of Transcription Factor NFAT by ADP-Ribosylation , 2008, Molecular and Cellular Biology.

[36]  T. Illig,et al.  Toward a major risk factor for atopic eczema: meta-analysis of filaggrin polymorphism data. , 2007, The Journal of allergy and clinical immunology.

[37]  V. Kuchroo,et al.  Th17: the third member of the effector T cell trilogy. , 2007, Current opinion in immunology.

[38]  Y. Suzuki,et al.  Poly(ADP-ribose) polymerase-1 inhibition prevents eosinophil recruitment by modulating Th2 cytokines in a murine model of allergic airway inflammation: a potential specific effect on IL-5. , 2007, The Journal of Immunology.

[39]  E. Fixman,et al.  Inhibition of Experimental Allergic Airways Disease by Local Application of a Cell-Penetrating Dominant-Negative STAT-6 Peptide1 , 2007, The Journal of Immunology.

[40]  K. Barnes,et al.  Cytokine modulation of atopic dermatitis filaggrin skin expression. , 2007, The Journal of allergy and clinical immunology.

[41]  S. Cho,et al.  Collaborator of Stat6 (CoaSt6)-associated Poly(ADP-ribose) Polymerase Activity Modulates Stat6-dependent Gene Transcription* , 2007, Journal of Biological Chemistry.

[42]  Yasuhiro Suzuki,et al.  Poly(ADP-ribose) Polymerase-1 Inhibition Prevents Eosinophil Recruitment by Modulating Th2 Cytokines in a Murine Model of Allergic Airway Inflammation: A Potential Specific Effect on IL-51 , 2006, The Journal of Immunology.

[43]  J. Yélamos,et al.  PARP‐2 deficiency affects the survival of CD4+CD8+ double‐positive thymocytes , 2006, The EMBO journal.

[44]  V. Schreiber,et al.  Poly(ADP-ribose): novel functions for an old molecule , 2006, Nature Reviews Molecular Cell Biology.

[45]  S. Sicherer,et al.  Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects. , 2006, The Journal of allergy and clinical immunology.

[46]  D. Hebenstreit,et al.  Signaling mechanisms, interaction partners, and target genes of STAT6. , 2006, Cytokine & growth factor reviews.

[47]  Colin N A Palmer,et al.  Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis , 2006, Nature Genetics.

[48]  M. Boothby,et al.  Selective potentiation of Stat-dependent gene expression by collaborator of Stat6 (CoaSt6), a transcriptional cofactor. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[49]  B. Aronow,et al.  Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. , 2006, The Journal of clinical investigation.

[50]  T. Kondratyuk,et al.  Cytokine Expression in Normal and Inflamed Esophageal Mucosa: A Study into the Pathogenesis of Allergic Eosinophilic Esophagitis , 2006, Journal of pediatric gastroenterology and nutrition.

[51]  S. Durual,et al.  Eotaxin-3/CCL26 gene expression in intestinal epithelial cells is up-regulated by interleukin-4 and interleukin-13 via the signal transducer and activator of transcription 6. , 2005, The international journal of biochemistry & cell biology.

[52]  Koichiro Nakamura,et al.  Interleukin‐4 and interleukin‐13 enhance CCL26 production in a human keratinocyte cell line, HaCaT cells , 2005, Clinical and experimental immunology.

[53]  M. Y. Kim,et al.  Poly(ADP-ribosyl)ation by PARP-1: 'PAR-laying' NAD+ into a nuclear signal. , 2005, Genes & development.

[54]  S. Cuzzocrea,et al.  Inhibition of Poly(ADP-Ribose) Polymerase Prevents Allergen-Induced Asthma-Like Reaction in Sensitized Guinea Pigs , 2004, Journal of Pharmacology and Experimental Therapeutics.

[55]  H. Ikeda,et al.  STAT6-mediated signaling in Th2-dependent allergic asthma: critical role for the development of eosinophilia, airway hyper-responsiveness and mucus hypersecretion, distinct from its role in Th2 differentiation. , 2004, International immunology.

[56]  S. Sicherer,et al.  Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2009. , 2004, The Journal of allergy and clinical immunology.

[57]  C. Szabó,et al.  Effects of poly(ADP-ribose) polymerase inhibition on inflammatory cell migration in a murine model of asthma. , 2004, Medical science monitor : international medical journal of experimental and clinical research.

[58]  M. Rothenberg,et al.  Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism. , 2003, Gastroenterology.

[59]  J. Travers,et al.  Cytokine Milieu of Atopic Dermatitis, as Compared to Psoriasis, Skin Prevents Induction of Innate Immune Response Genes 1 , 2003, The Journal of Immunology.

[60]  A. Ladurner Inactivating chromosomes: a macro domain that minimizes transcription. , 2003, Molecular cell.

[61]  M. Kaplan,et al.  Expression of a Constitutively Active Stat6 In Vivo Alters Lymphocyte Homeostasis with Distinct Effects in T and B Cells1 , 2003, The Journal of Immunology.

[62]  A. Boulares,et al.  Gene knockout or pharmacological inhibition of poly(ADP-ribose) polymerase-1 prevents lung inflammation in a murine model of asthma. , 2003, American journal of respiratory cell and molecular biology.

[63]  J. Darnell,et al.  Signalling: STATs: transcriptional control and biological impact , 2002, Nature Reviews Molecular Cell Biology.

[64]  D. Sheppard,et al.  Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma , 2002, Nature Medicine.

[65]  W. Ollier,et al.  Polymorphism in the STAT6 gene encodes risk for nut allergy , 2002, Genes and Immunity.

[66]  Luting Xu,et al.  Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. , 2001, The Journal of investigative dermatology.

[67]  M. Woisetschläger,et al.  Activation of Eotaxin-3/CCL26 Gene Expression in Human Dermal Fibroblasts Is Mediated by STAT6 , 2001, The Journal of Immunology.

[68]  P. Foster,et al.  Integrated Signals Between IL-13, IL-4, and IL-5 Regulate Airways Hyperreactivity , 2000, The Journal of Immunology.

[69]  Takashi Tanaka,et al.  The biology of Stat4 and Stat6 , 2000, Oncogene.

[70]  H. Kiyono,et al.  Systemically derived large intestinal CD4(+) Th2 cells play a central role in STAT6-mediated allergic diarrhea. , 2000, The Journal of clinical investigation.

[71]  E. Gelfand,et al.  The failure of STAT6-deficient mice to develop airway eosinophilia and airway hyperresponsiveness is overcome by interleukin-5. , 1999, American journal of respiratory and critical care medicine.

[72]  S. Akira,et al.  Abrogation of Bronchial Eosinophilic Inflammation and Airway Hyperreactivity in Signal Transducers and Activators of Transcription (STAT)6-deficient Mice , 1998, The Journal of experimental medicine.

[73]  M. Wills-Karp,et al.  Signal Transducer and Activator of Transcription Factor 6 (Stat6)-deficient Mice Are Protected from Antigen-induced Airway Hyperresponsiveness and Mucus Production , 1998, The Journal of experimental medicine.

[74]  U. Schindler,et al.  Requirements for interleukin-4-induced gene expression and functional characterization of Stat6 , 1996, Molecular and cellular biology.

[75]  W. Paul,et al.  Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted State6 gene , 1996, Nature.

[76]  S. Akira,et al.  Essential role of Stat6 in IL-4 signalling , 1996, Nature.

[77]  M. Kaplan,et al.  Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. , 1996, Immunity.

[78]  W. Paul,et al.  Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis , 1995, Molecular and cellular biology.

[79]  Q. Hamid,et al.  Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. , 1994, The Journal of clinical investigation.

[80]  V. Fried,et al.  MacroH2A, a core histone containing a large nonhistone region. , 1992, Science.

[81]  S. Sicherer,et al.  Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2014. , 2015, The Journal of allergy and clinical immunology.

[82]  F. Finkelman,et al.  Targeting IL-4/IL-13 signaling to alleviate oral allergen-induced diarrhea. , 2009, The Journal of allergy and clinical immunology.

[83]  É. Szabó,et al.  Poly(ADP-ribose) polymerase mediates inflammation in a mouse model of contact hypersensitivity. , 2009, The Journal of investigative dermatology.

[84]  Anand Gupte,et al.  Eosinophilic esophagitis. , 2009, World journal of gastroenterology.

[85]  I. Grzelewska-Rzymowska,et al.  [Airway remodeling in asthma]. , 2003, Pneumonologia i alergologia polska.

[86]  A Radbruch,et al.  Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. , 2000, Immunity.