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A Role for Stat-1 in Regulating Interleukin 10 Production Following Lps Challenge

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A Role for Stat-1 in Regulating Interleukin 10 Production Following Lps Challenge A ROLE FOR STAT-1 IN REGULATING INTERLEUKIN 10 PRODUCTION FOLLOWING LPS CHALLENGE DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University by Jeffrey Bryan VanDeusen, B.A. * * * * * The Ohio State University 2004 Dissertation Committee: Approved by Clay Marsh, MD Christoph Plass, PhD _______________________________ Michael A. Caligiuri, MD Denis Guttridge, PhD Adviser Department of Molecular Virology, Immunology, and Molecular Genetics ABSTRACT There have been substantial advances in understanding the events that regulate gene expression at the cellular and molecular level, however, there has been limited progress integrating this information to understand how biological systems function in vivo. Complementary DNA and protein microarray technologies in combination with sophisticated bioinformatics may eventually provide important insight into how biologic systems work in vivo. We hypothesized that assessments of such events in vivo would provide new insights into the immune response that could not be predicted or discovered ex vivo. Here, we describe the use of quantitative real time RT-PCR to serially quantify expression of a variety of pro- and anti-inflammatory cytokine genes in a number of individual tissues before, during, and after challenge with lipopolysaccharide (LPS). The data provide new insight into the heterogeneity of cytokine gene expression from organ to organ following infectious insult in vivo, as well as a greater understanding of cytokine regulation. For example, the anti- inflammatory cytokine interleukin-10 (IL-10) is thought to down-regulate the effects of the pro-inflammatory cytokine interferon gamma (IFN-γ) on monocyte activation following lipopolysaccharide (LPS) stimulation. However, the often-postulated reciprocal regulation of IL-10 gene expression by IFN-γ has not been studied in vivo. ii Here we serially quantify the expression of IL-10 before, during, and after an in vivo challenge with LPS or a gram-negative organism. In our system, we demonstrate that the regulation of IL-10 gene expression has at least two phases. The early induction occurs independent of the signal transducer and activator of transcription 1 (STAT-1), while a delayed active repression of IL-10 gene expression is critically dependent on STAT-1, most or all of which is independent of IFN-γ. Consistent with this, STAT-1 is absent from the IL-10 promoter during the early induction of the cytokine, but is bound to the IL-10 promoter in the delayed repression of the cytokine. Thus, STAT-1 binding to the IL-10 promoter is likely directly associated with STAT-1-mediated repression of IL-10 gene repression during infectious challenge with gram-negative organisms in vivo. This study provides new insights into the regulation of IL-10 following in vivo challenge with a gram-negative organism. iii What are the words to describe the feeling of watching a sunset over the ocean, the death of a loved one, or the warm sun on your face after a long winter? The English language, always so descriptive, fails utterly to portray these moments in all our lives. The words seem a dim reflection when held up to the events that inspire them. What are the words for graduate school? Some of them are hard work, inspiration, exhaustion, and elation. But they are pale. Dedicated to my loving family and friends In loving memory of Evelyn, my first girlfriend iv ACKNOWLEDGMENTS I wish to thank first and foremost my adviser, Michael Caligiuri, for his patience, guidance, enthusiasm and support during the last 6 years. His time and energy have helped shape my view of life and science. I also wish to thank Martin Guimond, whose arrival in the laboratory was a catalyst of change for my work. His technical expertise and discussions made much of my work possible. I thank my first student mentor in the lab, Todd Fehniger, for his help in teaching me how to be a graduate student in those early critical years. I thank Donna Bucci and Tamra Brooks for years of tireless work on my behalf. I thank my friends and collaborators Sameek Roychowdhury, Brian Becknell, Megan Cooper, Aharon Freud, and Bradley Blaser for their help and advice. I also would like to thank the many people whom are too numerous to mention whom have come through Dr. Caligiuri’s lab and helped me in my studies. Most importantly, I thank my family and Amanda for their love and support. This work was made possible by grants CA-68458, CA-65670, and P30CA-16058 from the National Institutes of Health. v VITA July 15, 1975..........................................Born Columbus, Ohio 1997........................................................B.A. Biology Summa Cum Laude Wittenberg University 1997-2004...............................................M.D./Ph.D. Candidate Fellow, Medical Scientist Program The Ohio State University, College of Medicine AWARDS AND FELLOWSHIPS 1993 Wittenberg University Honors Scholar. 1995 Outstanding Biology Student of the Year, Wittenberg University. 1996 Wittenberg University Presidential Scholar. 1996 Phi Beta Kappa. 1997 Summa Cum Laude. 1997-2004 Medical Scientist Program Fellow, The Ohio State University, College of Medicine 2000 First Place, Poster Presentation, Landacre Day Medical Student Research Forum, The Ohio State University. 2000 First Place, Poster Abstract, Medical Scientist Student Organization Research Day Conference Award, The Ohio State University. PUBLICATIONS 1. Fehniger TA, Shah MH, Turner MJ, VanDeusen JB, Whitman SP, Cooper MA, Suzuki K, Wechser M, Goodsaid F, Caligiuri MA. Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response. J Immunol 1999; 162(8):4511- 20. 2. Fehniger TA, Bluman EM, Porter MM, Mrozek E, Cooper MA, VanDeusen JB, Fankel SR, Stock W, Caligiuri MA. Potential mechanisms of human natural killer cell expansion in vivo during low dose IL-2 therapy. J Clin Invest. 2000; 106(1):117-24. 3. Fehniger TA, Suzuki K, Ponnappan A, VanDeusen JB, Cooper MA, Florea SM, Freud AG, Robinson ML, Durbin J, and Caligiuri MA. Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T Cells. J Exp Med 2001; 193(2): 219-232. vi 4. Fehniger TA, Suzuki K, VanDeusen JB, Cooper MA, Freud AG, and Caligiuri MA: Fatal leukemia in interleukin-15 transgenic mice. Blood Cells Mol Dis 2001; 27(1):223-230. 5. Tong HH, Chen Y, James M, VanDeusen JB, Welling DB, DeMaria TF: Expression of cytokine and chemokine genes by human middle ear epithelial cells induced by formalin-killed Haemophilus influenzae or its lipooligosaccharide htrB and rfaD mutants. Infect Immun. 2001 Jun;69(6):3678-84. 6. Cooper MA, Bush JE, Fehniger TA, VanDeusen JB, Waite RE, Liu Y, Aguila HL, Caligiuri MA: In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells. Blood. 2002 Nov 15;100(10):3633-8. 7. Nguyen KB, Salazar-Mather TP, Dalod MY, VanDeusen JB, Wei XQ, Liew FY, Caligiuri MA, Biron CA: Coordinated and distinct roles for IFN-alphabeta, IL-12, and IL-15 regulation of NK cell responses to viral infection. J Immunol. 2002 Oct 15;169(8):4279- 87. 8. VanDeusen JB, Caligiuri MA: New developments in anti-tumor efficacy and malignant transformation of human natural killer cells. Curr Opin Hematol. 2003 Jan; 10(1):55- 59. 9. Farag SS, VanDeusen JB, Fehniger TA, Caligiuri MA: Biology and clinical impact of human natural killer cells. Int J Hematol. 2003 Jul; 78(1):7-17. FIELDS OF STUDY Major Field: Molecular Virology, Immunology, and Medical Genetics Concentration in immunology vii TABLE OF CONTENTS Page Abstract.............................................................................................................................ii Dedication........................................................................................................................iv Acknowledgments............................................................................................................. v Vita...................................................................................................................................vi List of Figures..................................................................................................................ix 1. Introduction........................................................................................................... 1 Materials and Methods............................................................................ 17 Results..................................................................................................... 22 Discussion............................................................................................... 33 2. Literature Cited ................................................................................................... 54 viii LIST OF FIGURES Figure Page 1 LPS elicited cytokine production ....................................................................... 14 2 The LPS signaling pathway ................................................................................ 15 3 Interferon signaling............................................................................................. 16 4 Spleen cytokine production post LPS................................................................. 39 5 Liver cytokine production post LPS ..................................................................
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