{PPARγ [PPAR-gamma] as molecular target of epithelial functions in the gastrointestinal tract [Elektronische Ressource] / von Markus Schwab

Markus Schwab

Sujets

• Gesundheit

Informations

• Publié par: goethe_universitat_frankfurt_am_main
• Publié le: 01 janvier 2008
• Nombre de lectures: 80
• Langue: Deutsch
• Poids de l'ouvrage: 11 Mo

Extrait

PPARγ AS MOLECULAR TARGET OF
EPITHELIAL FUNCTIONS
IN THE GASTROINTESTINAL TRACT




Dissertation
zur Erlangung des Doktorgrades
der Naturwissenschaften





vorgelegt beim Fachbereich für
Biochemie, Chemie und Pharmazie
der Johann Wolfgang Goethe-Universität
in Frankfurt am Main






von
Markus Schwab
aus Rodgau (Hessen)



Frankfurt 2008

(D30)

























Vom Fachbereich Biochemie, Chemie und Pharmazie der
Johann Wolfgang Goethe-Universität als Dissertation angenommen.








Dekan: Prof. Dr. Harald Schwalbe

Gutachter: Prof. Dr. Dieter Steinhilber
Prof. Dr. Dr. Jürgen Stein



Datum der Disputation: 5. Mai 2008




























Meinen Eltern
















Es ist nicht genug, zu wissen,
man muss auch anwenden;

Es ist nicht genug zu wollen,
man muss auch tun.




Johann Wolfgang von Goethe

(Wilhelm Meisters Wanderjahre)








CONTENTS


I CONTENTS


I CONTENTS ........................................................................................................I
1 INTRODUCTION................................................................................................ 1
2 THE GASTROINTESTINAL ECOSYSTEM........................................................ 2
2.1 The intestinal epithelium and gastrointestinal diseases....................................................................... 2
2.1.1 The intestinal epithelium...................................................................................................................... 2
2.1.2 Gastrointestinal diseases 4
2.1.2.1 Inflammatory bowel disease....................................................................................................... 4
2.1.2.2 Colorectal cancer........................................................................................................................ 5
2.2 Peroxisome proliferator-activated receptor γ (PPAR γ) as a molecular target of epithelial
functions in the intestinal tract ............................................................................................................ 10
2.2.1 PPAR γ structure and activation ......................................................................................................... 10
2.2.2 Expression of PPAR γ in humans 12
2.2.3 Natural and synthetic ligands of PPAR γ............................................................................................ 13
2.2.4 Functions of PPAR γ........................................................................................................................... 14
2.2.5 Role of PPAR γ in colorectal cancer and inflammatory bowel disease .............................................. 15
2.3 The vitamin D receptor (VDR) as a molecular target of epithelial function in the intestinal
tract ........................................................................................................................................................ 17
2.3.1 VDR structure and activation............................................................................................................. 17
2.3.2 Ligands for VDR.18
2.3.3 Tissue distribution of VDR................................................................................................................ 20
2.3.4 Cellular functions of the VDR ........................................................................................................... 20
2.3.5 Role of VDR in colorectal cancer and inflammatory inflammatory bowel disease........................... 21
2.4 Drugs with promising characteristics to treat colorectal cancer and inflammatory bowel
disease .................................................................................................................................................... 22
2.4.1 Mesalazine.......... 22
2.4.2 Dietary Histone Deacetylase inhibitors.............................................................................................. 24
2.4.2.1 Butyrate..... 24
2.4.2.2 Sulforaphane............................................................................................................................. 26
I CONTENTS


2.5 Targets for nuclear hormone receptors involved in inflammation and cell cycling........................ 28
2.5.1 The caspase cascade........................................................................................................................... 28
2.5.2 Antimicrobial peptides....................................................................................................................... 30
2.5.2.1 Fundamentals............................................................................................................................ 30
2.5.2.2 Mechanisms of antimicrobial activity ...................................................................................... 31
2.5.2.3 Additional functions of antimicrobial peptides ........................................................................ 32
2.5.3 The nuclear factor NFκB ................................................................................................................... 33
3 AIM OF THE PRESENT INVESTIGATIONS.................................................... 35
4 METHODS........................................................................................................ 37
5 SUMMARY OF THE RESULTS ....................................................................... 39
5.1 Paper I: PPARγ is a key target of butyrate-induced caspase-3 activation in the colorectal
cancer cell line Caco-2 .......................................................................................................................... 40
5.2 Paper II: PPAR γ is a key target of mesalazine-mediated inhibition of cell growth and
induction of apoptosis in colon cancer cells ........................................................................................ 42
5.3 Additional results to Paper II: Enhanced anti-proliferative and pro-apoptotic effects of
mesalazine and butyrate in the colorectal cancer cell line Caco-2.................................................... 44
5.4 Paper III: Role of nuclear hormone receptors in butyrate-mediated up-regulation of the
antimicrobial peptide cathelicidin in epithelial colorectal cells
Paper IV: The dietary histone deacetylase inhibitor sulforaphane induces human beta
defensin-2 in intestinal epithelial cells ................................................................................................. 48
5.5 Paper V: Involvement of different nuclear hormone receptors in butyrate-mediated
inhibition of inducible NFκB signalling .............................................................................................. 51
6 DISCUSSION ................................................................................................... 54
6.1 Importance of PPAR γ in mesalazine’s and butyrate’s pro-apoptotic abilities................................ 54
6.2 Crucial role of VDR in HDAC-mediated induction of the anti-microbial peptides HBD-2
and LL-37 .............................................................................................................................................. 61
6.3 Stimuli-dependent participation of PPARγ and VDR in butyrate-mediated suppression of
cytokine-induced NFκB activation ...................................................................................................... 66
II CONTENTS


7 SUMMARY - ACHIEVEMENT OF THIS WORK AND OUTLOOK................... 72
8 ZUSAMMENFASSUNG ................................................................................... 74
9 REFERENCES................................................................................................. 80
10 APPENDIX ..................................................................................................... 101
10.1 Abbreviations ...................................................................................................................................... 101
10.2 List of figures and tables .................................................................................................................... 103
11 CURRICULUM VITAE.................................................................................... 105
12 ZAFES-ZERTIFICAT...................................................................................... 110
13 EIDESSTATTLICHE VERSICHERUNG......................................................... 111
14 DANKSAGUNG ..........................................................................