Molecular pathogenesis of liver disease: an approach to hepatic inflammation, cirrhosis and liver transplant tolerance.
The hallmarks of chronic liver diseases are chronic inflammation, cellular damage, regeneration and fibrosis. An appreciation of intrahepatic molecular expression patterns in normal and diseased liver provides clues for understanding pathogenic pathways whilst studies of the structure and function of molecules implicated in liver disease provide insights into their potential as therapeutic targets. We have examined the expression, function, molecular structure and structure-function relationships of type IV dipeptidyl aminopeptidases. In particular, the roles of CD26/DPPIV in T-cell proliferation and chemotaxis and of fibroblast activation protein in human cirrhosis are discussed. We have investigated the pathogenesis of liver disease by characterising patterns of cytokine and growth factor expression in experimental and human cirrhosis. We have quite recently expanded this approach to use differential gene expression analyses to elucidate overall pathways of gene activation and suppression in human cirrhosis. In addition, our detailed molecular and cellular studies of the mechanisms of spontaneous liver transplant tolerance have generated novel insights into this process. This review touches on these diverse aspects of liver function and disease.
McCaughan
G W
GW
Royal Prince Alfred Hospital, Centenary Institute of Cancer Medicine and Cell Biology and The University of Sydney, Australia. G.McCaughan@centenary.usyd.edu.au
Gorrell
M D
MD
Bishop
G A
GA
Abbott
C A
CA
Shackel
N A
NA
McGuinness
P H
PH
Levy
M T
MT
Sharland
A F
AF
Bowen
D G
DG
Yu
D
D
Slaitini
L
L
Church
W B
WB
Napoli
J
J
D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm; D017209:Apoptosis; D001665:Binding Sites; D014408:Biomarkers, Tumor; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000502:physiology*; D010450:Endopeptidases; D018093:Gelatinases; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006085:Graft Survival; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D006505:Hepatitis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance; D008103:Liver Cirrhosis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D016031:Liver Transplantation / Q000276:immunology; D008213:Lymphocyte Activation; D008565:Membrane Proteins; D008958:Models, Molecular; D051381:Rats; D012697:Serine Endopeptidases / Q000502:physiology; D013329:Structure-Activity Relationship; D013382:Subtraction Technique; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology; D015533:Transcriptional Activation; D000099167:Fibroblast Activation Protein Alpha
D000243:Adenosine Deaminase; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D016207:Cytokines; D018819:Dipeptidyl Peptidase 4; D010450:Endopeptidases; D018093:Gelatinases; D006133:Growth Substances; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha