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Molecular Basis of Upregulation of IL-17 in Estrogen Model of Inflammation Deena Khan Dissertation Submitted to the Faculty of T

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Molecular Basis of Upregulation of IL-17 in Estrogen Model of Inflammation Deena Khan Dissertation Submitted to the Faculty of T Molecular Basis of Upregulation of IL-17 in Estrogen Model of Inflammation Deena Khan Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical and Veterinary Sciences S. Ansar Ahmed Committee Chair Liwu Li William R. Huckle Christopher M. Reilly June 20th, 2012 Blacksburg, Virginia Keywords: Interleukin, IL-17, estrogen, immune, induction, response Copyright All Chapters © 2012 by Deena Khan Chapter 4© 2010 by John Wiley and Son, Inc. ABSTRACT Molecular Basis of Upregulation of IL-17 in Estrogen Model of Inflammation by Deena Khan Interleukin-17 (IL-17) plays a major role in inflammation by regulating the induction of various proinflammatory genes, which aid in the recruitment and activation of neutrophils. Although IL-17 is considered to be protective in infection, overproduction of IL-17 in conditions like autoimmune diseases has been shown to aggravate these diseases and contribute to tissue injury. One of the principal focus of our laboratory is to decipher molecular mechanisms involved in inflammatory cytokine regulation and response in inflammatory disorders. To study this aspect, we employ a murine model of pro-inflammation induced by exposure to a natural immunomodulator, estrogen. In this novel study, we have comprehensively investigated the effect of estrogen on IL-17 induction, an aspect not studied thus far. We are the first to demonstrate that estrogen increases the ability of lymphocytes to secrete IL-17A, and its isoforms IL-17F, IL-17A/F. In addition to the cytokine levels, the percentages of IL-17+ cells are also increased by estrogen. Impressively, we found that estrogen fine tunes the balance of multiple transcription factors/signaling pathways. Estrogen upregulates IL-17 by promoting the activity and expression of positive regulators (RORγt, RORα, NF-κB, JAK-2) and decreases the activity and/or expression of negative regulators (IRF8, ETS-1). In addition, we found that estrogen epigenetically regulates IL-17 induction by miRNAs (miR-326 and miR-223). We also found that majority of IL-17 positive cells are CD8+ suggesting that estrogen-mediated IL-17 induction is predominantly from Tc17 cells. This is possibly due to increased proliferation of CD8+ cells from estrogen-treated mice, as demonstrated by CFSE cell proliferation assay. Furthermore, estrogen also enhances the ability of IL-17-target cells to release proinflammatory molecules when exposed to IL-17. Together, this is the first study to comprehensively show that estrogen calibrates transcription factors and miRNAs to enhance IL-17 induction and promote IL-17 response. This dissertation work will provide a platform to continue further research in estrogen modulation of IL-17 in inflammation and disease conditions. iii Dedication To my Parents iv Acknowledgements I feel truly blessed to be given the opportunity to pursue my graduate studies in state of art Virginia Polytechnic Institute and State University. I express my humble gratitude to all the people I met here in Virginia Tech and United States. I am highly honored to have such a fulfilling learning experience. Foremost, I would like to express my sincere gratitude to my advisor Dr. S. Ansar Ahmed for the continuous support of my Ph.D study and research, for his patience, motivation, enthusiasm, and immense knowledge. His invaluable advice always helped me whenever I was stuck in research problems and always gave me new ideas to find solutions of any problem I encountered. He helped me think independently and developed confidence in me and showed me how to interpret scientific data in different ways. I could not have imagined having a better advisor and mentor for my Ph.D. study To my esteemed committee, I express my sincere gratitude to Dr. Liwu Li, Dr. Christopher R. Reilly, and Dr. William R. Huckle for all the intellectual discussions and your inputs and suggestions were very helpful in designing experiments. Special thanks to Dr. Robert Gogal and Dr. Wen Li for their advice and assistance in carrying research. I am highly grateful to Dr. Roger Avery for supporting my graduate research assistantship along with travel grant support and I was able to interact with eminent people in different fields of science and technology. I am also grateful to the wonderful staff in Research and Graduate Studies esp. to Becky Jones and also to Monica Taylor and Patty Goudy in Department of Biomedical Science and Pathobiology for all their help. I am thankful to all current and previous members of our research group especially Dr. Rujuan Dai, Bettina Heid, and Catharine Cowan. Dr. Dai’s guidance and expertise in research helped me tremendously in all stages of my research. You have a special place in my heart and your friendship, generosity and kindness will always be with me for whole life. Special thanks to Bettina and Catharine for their help in all of my animal experiments, collection of tissues and processing of samples. Thank you for running lab so efficiently. I feel obliged to all those people v who were involved in making this project possible including Melissa Makris for all flow analysis and lab animal care staff, lab animal veterinarian and glassware cleaning services personnel and above all the lives of experimental mice that were used in this dissertation. I express my sincere gratitude to Mrs. Asma Ahmed and Mrs. Nikhat Rizvi for all their prayers and special affection for me. I am very indebted to my friends here in Blacksburg and all those in India for all their good wishes and special moments that we shared which made my stay here pleasant and enjoyable I dedicate this dissertation to my father Dr. Abdul Qayyum Khan and my mother Mrs. Shehla Khan for their unconditional love, support, encouragement, sacrifice and invaluable prayers throughout my life. It is because of them I am here at this stage of life. I owe my deepest gratitude and also dedicate this dissertation to my maternal grandparents Late Chaudhary Mohammad Arif and Late Mrs. Shahjahan Begum and paternal grandparents Late Zafar Alam Khan and Late Mrs. Maqsoodan Khan for their sacrifices and prayers throughout their life which has a very big role in making this journey possible. Special thanks are reserved to my sister Dr. Yusra Khan, brother-in-law Dr. Aslam Baig and brothers Kunwar Mohammad Hussain Khan, Kunwar Mohammad Taha Khan and niece Amna for their constant love and wishes. I was very fortunate of having my family so nearby which very few international students get this opportunity. I express my sincere gratitude to my sister Dr. Tila Khan, brother-in-law Dr. Mohammed Rabius Sunny for all their untimely help, and support in every aspect of personal and professional life here in Blacksburg. This journey would not have been possible without the support of my husband Syed Makhmoor Mazahir who stood by me through the good and bad times, left his rising career for me and supported me constantly with his unconditional and undemanding love and care and my precious little girl, Sarah whose presence made this entire program a wonderful experience. Lastly, I would like to thank my mother-in-law Mrs. Najma Mazahir Ali for her help and support and for making my life so comfortable, easy and enjoyable. vi Table of Contents Page # ABSTRACT ............................................................................................................................... ii Dedication ................................................................................................................................. iv Acknowledgements ................................................................................................................... v Table of Contents .................................................................................................................... vii List of Figures .......................................................................................................................... xii Chapter 1 Estrogen and Signaling in the Cells of Immune System ..................................... 1 Abstract ................................................................................................................................... 1 Sources and Biosynthesis of Estrogens: ................................................................................. 1 Estrogen Receptors in the cells of the Immune System:......................................................... 5 Estrogen-receptor mediated Cell signaling. ............................................................................ 9 Estrogen-mediated regulation of pro-inflammatory cytokines ............................................. 12 Cytokines from Innate Immune cells ........................................................................ 12 Cytokines from cells of the adaptive immune system .............................................. 15 Cytokines from Tregs cells ....................................................................................... 16 Contrasting Influence of Estrogen on MS and SLE.............................................................. 18 miRNA and Estrogen ............................................................................................................ 23 Conclusion ............................................................................................................................ 25 References ............................................................................................................................
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