Molecular Consequences of Estrogen-Induced Interferony

Summary

Principal Investigator: S A Ahmed
Abstract: Sex hormones, such as estrogens, are believed to play a major role in gender-based differential immune competence and autoimmunity. One mechanism by which estrogens may influence the immune system is by regulating cytokine levels. We have recently reported that estrogen-treated wild type C57BL/6 mice have increased IFNy mRNA and protein levels. This grant proposal is aimed at mechanistically studying how estrogen alters the production of lFNy and the molecular consequences of increased IFNz Estrogen-induced IFN'/is significant, since IFNy is a "master" cytokine with physiological effects on nearly all ceils of the immune system: it is involved in resistance against intracellular infections, and in pathological effects of many autoimmune and inflammatory diseases. The hypothesis of this proposal is that increased IFNy in estrogen-treated mice is due to the promotion of increased numbers of specific IFNy secreting cells, an enhanced response to IFN[unreadable] -promoting cytokines and/or eo-stimulatory signals. A consequence of this increased IFNy will be altered cellular and molecular functions of IFN[unreadable] target cells. This may be evident as increased expression of IFNy responsive genes and molecules, altered patterns of apoptosis and changes in susceptibility to autoimmunity. _ of this proposal will examine the molecular basis for estrogen-induced IFNy. _ will determine whether responsiveness of IFNy-target ceils to IFNy is altered in estrogen-treated mice, with regard to STAT1 activation, IFNy-responsive genes, and expression of IRF-1, IRF-2, Cox-2, and MHC molecules. _ will investigate whether increased survival oflymphocvtes from estrogen-treated mice is due to IFNy inducible nitric oxide, by using estrogen-treated wild type, IFNy knockout, and iNOS knockout mice. _1 will address whether estrogen treated non-autoimmune mice are prone to develop selected types ofinduced-autoimmuni_ and whether this is due to IFNy. This proposal is novel since it will provide a mechanistic-based understanding of how estrogen promotes IFNy and its consequences at molecular, cellular and organismal levels. The proposal will benefit the future understanding of human health, especially with regard to gender-based immune diseases. PERFORMANCESITE(S) (organizationc, ity,state) Center for Molecular Medicine and Infectious Diseases (CMMID) Dept. of Biomedical Sciences and Pathobiology Virginia-Maryland Regional College of Vet. Med. Virginia Tech University 1410, Prices Fork Road, Blacksburg, VA 24061 KEYPERSONNEL.See instructions. Usecontinuationpagesas neededto providetherequiredinformationin theformat shownbelow. StartwithPrincipaIlnvestigator.Listallotherkeypersonnelinalphabeticaolrder,lastnamefirst. Name Organization Role onProject Ahrned, Ansaf Virginia Tech Principal Investigator Christadcss, P. Univ. Texas Med. Branch Co-Investigator Elvinger, F. Virginia Tech Co-Investigator Huckle, W.R. Virginia Tech Co-Investigator Ju, Shyr-Te Boston University Co-Investigator King, C. Virginia Tech Postdoctoral Fellow Kruzelock, R. Virginia Tech Co-Investigator Lengi, A. Virginia Tech Lab Specialist Saunders, G. Virginia Tech Co-Investigator DisclosurePermissionStatement.APPlicableto SBIR/STTROnly. See instructions[]. Yes [] No + PHS398(Rev.05101) Page_2 FormPage2 * ! Principal Investigator/Program Director (Last, first, middle): Ahrned. Ansar The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page ......................................................................................................................................................... 1 Description,
Funding Period: 2002-12-15 - 2009-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Serine protease inhibitor, 4-(2-aminoethyl)-benzene sulfonyl fluoride, impairs IL-12-induced activation of pSTAT4β, NFκB, and select pro-inflammatory mediators from estrogen-treated mice
    Ebru Karpuzoglu
    College of Veterinary Medicine, Department of Anatomy and Radiology, University of Georgia, Athens, GA 30621, USA
    Immunobiology 216:1264-73. 2011
  2. pmc MicroRNA, a new paradigm for understanding immunoregulation, inflammation, and autoimmune diseases
    Rujuan Dai
    Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathology, Virginia Maryland Regional College of Veterinary Medicine, Virginia Tech Virginia Polytechnic Institute and State University, Blacksburg, VA 24061 0342, USA
    Transl Res 157:163-79. 2011
  3. pmc Identification of a common lupus disease-associated microRNA expression pattern in three different murine models of lupus
    Rujuan Dai
    Center for Molecular Medicine and Infectious Diseases CMMID, Department of Biomedical Sciences and Pathology, Virginia Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America
    PLoS ONE 5:e14302. 2010
  4. pmc Estrogen increases, whereas IL-27 and IFN-gamma decrease, splenocyte IL-17 production in WT mice
    Deena Khan
    Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathobiology, Virginia Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060 0342, USA
    Eur J Immunol 40:2549-56. 2010
  5. pmc Estrogen regulates transcription factors STAT-1 and NF-kappaB to promote inducible nitric oxide synthase and inflammatory responses
    Rujuan Dai
    Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathobiology, Virginia Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA
    J Immunol 183:6998-7005. 2009
  6. pmc Signal transducer and activation of transcription (STAT) 4beta, a shorter isoform of interleukin-12-induced STAT4, is preferentially activated by estrogen
    Ebru Karpuzoglu
    Department of Biomedical Sciences, Center for Molecular Medicine and Infectious Diseases, Virginia Maryland Regional College of Veterinary Medicine, Virginia Tech, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA
    Endocrinology 150:1310-20. 2009
  7. pmc Suppression of LPS-induced Interferon-gamma and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: a novel mechanism of immune modulation
    Rujuan Dai
    Department of Biomedical Sciences and Pathology, Center for Molecular Medicine and Infectious Diseases, Virginia Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA24061 0342, USA
    Blood 112:4591-7. 2008
  8. ncbi Despite inhibition of nuclear localization of NF-kappa B p65, c-Rel, and RelB, 17-beta estradiol up-regulates NF-kappa B signaling in mouse splenocytes: the potential role of Bcl-3
    Rujuan Dai
    Department of Biomedical Sciences and Pathology, Virginia Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA
    J Immunol 179:1776-83. 2007
  9. ncbi Estrogen selectively regulates chemokines in murine splenocytes
    Andrea J Lengi
    Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathology, Virginia Maryland Regional College of Veterinary Medicine, Virginia Tech, 1410 Prices Fork Road, Blacksburg, VA 24061 0342, USA
    J Leukoc Biol 81:1065-74. 2007
  10. ncbi 17beta-estradiol downregulates interferon regulatory factor-1 in murine splenocytes
    Andrea J Lengi
    Department of Biomedical Sciences and Pathology, Virginia Maryland Regional College of Veterinary Medicine, 1410 Prices Fork Road, Blacksburg, VA 24061 0342, USA
    J Mol Endocrinol 37:421-32. 2006

Scientific Experts

  • Rujuan Dai
  • Ebru Karpuzoglu
  • S Ansar Ahmed
  • Rebecca A Phillips
  • Andrea J Lengi
  • Robert M Gogal
  • Deena Khan
  • Sattar Ansar Ahmed
  • Carmine Graniello
  • Jillian B Fenaux
  • Francois Elvinger

Detail Information

Publications13

  1. ncbi Serine protease inhibitor, 4-(2-aminoethyl)-benzene sulfonyl fluoride, impairs IL-12-induced activation of pSTAT4β, NFκB, and select pro-inflammatory mediators from estrogen-treated mice
    Ebru Karpuzoglu
    College of Veterinary Medicine, Department of Anatomy and Radiology, University of Georgia, Athens, GA 30621, USA
    Immunobiology 216:1264-73. 2011
    ..These findings provide a new understanding of inflammation and inhibition of serine proteases has important implications for designing novel therapeutic strategies for a broad range of inflammatory diseases...
  2. pmc MicroRNA, a new paradigm for understanding immunoregulation, inflammation, and autoimmune diseases
    Rujuan Dai
    Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathology, Virginia Maryland Regional College of Veterinary Medicine, Virginia Tech Virginia Polytechnic Institute and State University, Blacksburg, VA 24061 0342, USA
    Transl Res 157:163-79. 2011
    ....
  3. pmc Identification of a common lupus disease-associated microRNA expression pattern in three different murine models of lupus
    Rujuan Dai
    Center for Molecular Medicine and Infectious Diseases CMMID, Department of Biomedical Sciences and Pathology, Virginia Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America
    PLoS ONE 5:e14302. 2010
    ..Therefore, it is important to determine miRNA dysregulation and its pathogenic contribution in autoimmune diseases, an aspect not adequately addressed thus far...
  4. pmc Estrogen increases, whereas IL-27 and IFN-gamma decrease, splenocyte IL-17 production in WT mice
    Deena Khan
    Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathobiology, Virginia Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060 0342, USA
    Eur J Immunol 40:2549-56. 2010
    ..Furthermore, inhibition of JAK-2 by AG490 suppressed IL-17 but not ROR gamma t expression, suggesting that other transcription factors are also critical in estrogen-mediated upregulation of IL-17...
  5. pmc Estrogen regulates transcription factors STAT-1 and NF-kappaB to promote inducible nitric oxide synthase and inflammatory responses
    Rujuan Dai
    Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathobiology, Virginia Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA
    J Immunol 183:6998-7005. 2009
    ..Together, our data reveal a novel molecular mechanism of estrogen-mediated promotion of inflammatory responses, which involves posttranslational modification of STAT-1 and NF-kappaB proteins...
  6. pmc Signal transducer and activation of transcription (STAT) 4beta, a shorter isoform of interleukin-12-induced STAT4, is preferentially activated by estrogen
    Ebru Karpuzoglu
    Department of Biomedical Sciences, Center for Molecular Medicine and Infectious Diseases, Virginia Maryland Regional College of Veterinary Medicine, Virginia Tech, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA
    Endocrinology 150:1310-20. 2009
    ..These novel findings are likely to provide new knowledge with regard to estrogen regulation of inflammation...
  7. pmc Suppression of LPS-induced Interferon-gamma and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: a novel mechanism of immune modulation
    Rujuan Dai
    Department of Biomedical Sciences and Pathology, Center for Molecular Medicine and Infectious Diseases, Virginia Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA24061 0342, USA
    Blood 112:4591-7. 2008
    ..Our data are the first to demonstrate the selective regulation of miRNA expression in immune cells by estrogen and are indicative of an important role of miRNAs in estrogen-mediated immune regulation...
  8. ncbi Despite inhibition of nuclear localization of NF-kappa B p65, c-Rel, and RelB, 17-beta estradiol up-regulates NF-kappa B signaling in mouse splenocytes: the potential role of Bcl-3
    Rujuan Dai
    Department of Biomedical Sciences and Pathology, Virginia Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA
    J Immunol 179:1776-83. 2007
    ..The novel findings of differential regulation of NF-kappaB proteins by estrogen provide fresh insight into potential mechanisms by which estrogen can regulate NF-kappaB-dependent immunological events...
  9. ncbi Estrogen selectively regulates chemokines in murine splenocytes
    Andrea J Lengi
    Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathology, Virginia Maryland Regional College of Veterinary Medicine, Virginia Tech, 1410 Prices Fork Road, Blacksburg, VA 24061 0342, USA
    J Leukoc Biol 81:1065-74. 2007
    ..These studies provide novel data indicating that estrogen may promote inflammatory conditions by altering the levels of chemokines, providing evidence for an additional mechanism by which estrogens can regulate inflammation...
  10. ncbi 17beta-estradiol downregulates interferon regulatory factor-1 in murine splenocytes
    Andrea J Lengi
    Department of Biomedical Sciences and Pathology, Virginia Maryland Regional College of Veterinary Medicine, 1410 Prices Fork Road, Blacksburg, VA 24061 0342, USA
    J Mol Endocrinol 37:421-32. 2006
    ..These studies are the first to show that estrogen regulates IFN-gamma-inducible IRF-1 in lymphoid cells, a finding that may have implications to IFN-gamma-regulated immune and vascular diseases...
  11. pmc IFN-gamma-inducing transcription factor, T-bet is upregulated by estrogen in murine splenocytes: role of IL-27 but not IL-12
    Ebru Karpuzoglu
    Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathobiology, Virginia Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061, USA
    Mol Immunol 44:1808-14. 2007
    ..Given that T-bet is a potent inducer of IFN-gamma, these studies may lead to new lines of investigation in relation to many female-predominant autoimmune diseases and inflammatory disorders...
  12. ncbi Estrogen regulation of nitric oxide and inducible nitric oxide synthase (iNOS) in immune cells: implications for immunity, autoimmune diseases, and apoptosis
    Ebru Karpuzoglu
    Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathobiology, Virginia Maryland Regional College of Vet Med, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
    Nitric Oxide 15:177-86. 2006
    ..Given the increasing importance of immune-tissue-derived iNOS in health and disease, studies on estrogen-induced regulation of iNOS may offer a better understanding of diseases and aid in devising new therapeutic interventions...
  13. ncbi Estrogen up-regulates inducible nitric oxide synthase, nitric oxide, and cyclooxygenase-2 in splenocytes activated with T cell stimulants: role of interferon-gamma
    Ebru Karpuzoglu
    Department of Biomedical Sciences and Pathobiology, Center for Molecular Medicine and Infectious Diseases, Virginia Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, 24061, USA
    Endocrinology 147:662-71. 2006
    ..These findings may have wide implications to immunity and inflammatory disorders including female-predominant autoimmune diseases...