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University of Cincinnati UNIVERSITY OF CINCINNATI January 3, 2002 I, Arthur M. Barrie, III, hereby submit this as part of the requirements for the degree of: Doctorate of Philosophy (Ph.D.) in: the Graduate Program in Molecular and Developmental Biology It is entitled: " The Role and Regulation of the Anti-Inflammatory Mouse Apolipoprotein J Gene" Approved by: Dr. Bruce Aronow, Ph.D. Dr. John Bissler, M.D. Dr. Robert Colbert, M.D., Ph.D. Dr. Sandra Degen, Ph.D Dr. Jun Ma, Ph.D. THE ROLE AND REGULATION OF THE ANTI-INFLAMMATORY MOUSE APOLIPOPROTEIN J GENE A dissertation submitted to the Division of Research and Advanced Studies of the University of Cincinnati in partial fulfillment of the requirements for the degree of DOCTORATE OF PHILOSOPHY (Ph.D.) in the Graduate Program in Molecular and Developmental Biology of the College of Medicine 2001 by Arthur M. Barrie, III B.S., The Ohio State University, 1995 Committee chair: Dr. Bruce Aronow, Ph.D. Abstract Apolipoprotein J (apoJ) is a secreted protein with chaperone homology found in vertebrates and is induced and deposited in both physiologic and pathologic states. ApoJ is hypothesized to be a novel extracellular heat shock protein. I characterized the stress response regulation of the mouse apoJ gene. Cell culture experiments verified the essential roles of an apoJ promoter heat shock element (HSE) and the heat shock transcription factor 1 (HSF1) in heat shock-dependent apoJ gene activation. My studies identified multiple cooperating cis-elements, including a promoter activator protein-1 (AP-1) binding motif, an intron 1 enhancer, and a downstream silencer, that together conferred the full range of apoJ gene expression. I also sought to determine the function of the mouse apoJ gene in response to immune complex- mediated glomerulonephritis. I observed that apoJ deficiency exacerbated renal inflammation and predisposed to rapidly progressive disease. My data also revealed that apoJ levels affected the differentiation of the immune response. These experiments establish apoJ as a highly evolved heat shock protein that suppresses inflammation and immune-mediated tissue injury. Dedication I dedicate this thesis with love to my wife, Amy Felice, who has blessed me with endless love and support during my trials and tribulations as a graduate student. I am very appreciative of the significant sacrifices she has made out of respect for my personal goals. I also dedicate this thesis to my parents, Sally and Boyd Frazier, and Arthur Barrie, Jr. My achievements are directly attributable to their love, patience, wisdom, and guidance, and for that I am eternally grateful. Lastly, I would like to humbly acknowledge Our Almighty Creator, whose handiwork and intellect are revealed in every scientific endeavor. Table of Contents pages General Introduction 5-26 Chapter 1 Cooperation between Multiple Cis-Elements of the Mouse Apolipoprotein J Locus Is Required for Inducible Gene Expression 27-102 Chapter 2 Suppression of Immune Complex-Mediated Glomerulonephritis by Mouse Apolipoprotein J 103-160 Final Discussion The Heat Shock Response and Mouse Apolipoprotein J 161-164 Bibliography 165-199 1 Figures and Tables page General Introduction 1. Map of the mouse apoJ gene and protein coding sequences. 22 2. Postulated structure of the mammalian apoJ protein. 24 3. Regulatory factors of the mammalian apoJ gene promoter. 26 Chapter 1 1. Schematic diagram of mouse apoJ gene sequences and reporter constructs. 66 Table 1. Wild-type and mutant mouse apoJ gene promoter element sequences. 68 2. Basal expression profiles of transfected mouse apoJ gene wild-type and mutant reporter constructs. 70 3. Northern blot analysis of apoJ gene induction in mink lung epithelial cells (CCL-64). 72 4. TGFβ responsiveness of transient transfected wild-type and mutant mouse apoJ gene reporter constructs in CCL64 cells. 74 5. Northern blot analysis of apoJ gene induction in mouse fibroblasts (NIH-3T3). 76 6. Heat shock inducibility of transient transfected wild-type and mutant mouse apoJ gene reporter constructs in NIH-3T3 cells. 78 7. Time course study of transient transfected wild-type and mutant mouse apoJ reporter gene expression during heat shock. 80 8. HSF1-transactivation of transient transfected wild-type and mutant mouse apoJ gene reporter constructs in NIH-3T3 cells. 82 9. Heat shock induction of the mouse apoJ gene CAT-1 WT reporter construct in HSF1-deficient and wild-type mouse fibroblasts. 84 2 10. RT-PCR analysis of mouse apoJ gene heat shock induction in HSF1-deficient and wild-type mouse fibroblasts. 86 11. Role of intron 1 enhancer during stress induction. 88 12. Role of downstream apoJ gene silencer on stress-mediated induction. 90 13. Transgenic analysis of mouse apoJ reporter genes in response to heat shock. 92 14. Reporter gene dissection of mouse apoJ gene intron 6. 94 15. Characterization of mouse apoJ reporter gene with partial intron 6 deletion. 96 16. Promoter-mediated induction of the mouse apoJ gene. 98 17. Computer sequence analysis of the mouse apoJ gene intron 6 silencer. 100 18. Model of mouse apoJ gene regulation mediated by multiple putative cis-elements. 102 Chapter 2 1. Scoring nomenclature for glomerular histopathology. 136 Table 1. Histopathological assessment of renal sections. 138 Table 2. Physiologic assessment of apoferrtin-treated mice. 140 2. Immunohistochemistry for IgG, IgM, and IgA in representative glomeruli. 142 3. Immunohistochemistry for complement proteins C3 and C9 in representative glomeruli. 144 4. Electron microscopic analysis of immune complexes in representative glomeruli. 146 5. Characteristic electron microscopic glomerular images. 148 6. Serum complement C3 levels in wild-type and apoJ-deficient treated mice in trials 1 and 3. 150 7. Anti-apoferritin IgG1 and total IgG1 serum antibody levels. 152 3 8. Anti-apoferritin IgG2a and total IgG2a serum antibody levels. 154 9. Ratios of Th2 versus Th1 serum antibodies. 156 10. Postulated mechanisms of apoJ-mediated suppression of immune complex-mediated glomerulonephritis. 158 11. Postulated regulatory role for apoJ in Th1 versus Th2 immune response differentiation. 160 4 General Introduction 5 ApoJ biological roles. The apolipoprotein J (apoJ) gene encodes an intriguing protein with a striking expression pattern and numerous biological properties. ApoJ protein was first purified from ram testes fluid, and characterized as a pro-cell aggregation factor (1). Since that initial study, varied functions or processes have been attributed to apoJ activity based on its tissue distribution and protein-binding partners. Proposed apoJ roles include complement regulation, cell death modulation, lipid transport, membrane protection, and protein chaperone activity (2-7). ApoJ expression appears to be a fundamental feature of many tissues undergoing development or remodeling, suggesting that apoJ is an essential morphogenic factor. In vitro, apoJ promotes cell aggregation of multiple cell types including spermatozoa, Sertoli cells, erythrocytes, and renal epithelial cells (1, 8, 9). In vivo, apoJ may facilitate cell-cell and cell- substratum interactions during tissue development, and may maintain such contacts during tissue damage such as in renal tubular injury. In renal cell culture, cytoskeletal alterations that disrupt cell-cell and cell-matrix interactions are associated with increased apoJ message levels (9). Sertoli cells induce apoJ expression at the time of cell attachment, and inhibition of apoJ activity correlates with anchorage-dependent apoptosis (10). ApoJ also promotes the formation of vascular smooth muscle cell nodules in tissue culture, which have been implicated in the pathogenesis of atherosclerosis (11). Most bodily fluids are rich in apoJ protein, often coupled to various lipoprotein particles such as HDL and VHDL. The relationships between apoJ and lipoprotein particles suggest that apoJ is involved in lipid transport. Compatible with its developmental and injury-inducible expression pattern, apoJ may facilitate lipid recycling at dynamic tissue sites. ApoJ induces cholesterol and phospholipid efflux from macrophage-foam cells in vitro, and associates with the 6 secreted cholesterol in the culture medium (12). Thus, apoJ may suppress lipid-mediated diseases such as atherosclerosis by promoting lipid export. ApoJ may modulate other lipoprotein activities besides lipid transport. HDL particles generally protect against tissue injury by suppressing inflammation and oxidative stress via the activity of various co-factors such as platelet-activating factor acetylhydrolase, ceruloplasmin, and paraoxonase (13, 14). ApoJ is induced in a wide array of inflammatory lesions and, in the context of HDL, may represent a supplementary anti-inflammatory co-factor. ApoJ levels are often inversely correlated with levels of the anti-oxidant HDL co-factor, paraoxonase, in response to oxidized lipids (15, 16). ApoJ is also co-deposited with paraoxonase in inflammatory atherosclerotic lesions (14). Considering the hydrophobic binding nature of apoJ, the protein may clear lipid-based toxic molecules generated during developmental or pathologic apoptosis. Fibroblasts in cell culture induce apoJ expression upon exposure to a wide variety of cellular lipid debris, including apoptotic vesicles, disrupted cells, and membrane remnants (17). The hydrophobic bias of apoJ may also aid in the protection of cellular membranes against harmful bioactive fluids and complement-mediated cell lysis. This theory is compatible with the robust expression of apoJ along fluid-tissue
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