Impaired liver regeneration with humoral and genetic disturbances in urinary trypsin inhibitor-deficient mice.
OBJECTIVE
Urinary trypsin inhibitor (UTI) is an innate anti-inflammatory regulator. It can block the release of inflammatory factors, prevent the cascade reaction of cytokines and inhibit excessive activation of leukocytes. Liver regeneration (LR) is a dynamic molecular phenomenon without inflammation. Many cytokines, including tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), have been implicated in regulating LR. However, the role of UTI in LR is totally unknown. The aim of this study was to elucidate the role of UTI in LR using genetically UTI-deficient mice.


METHODS
We performed 68% hepatectomy, comparing UTI (-/-) and UTI (+/+) mice. Recovery of liver weight was recorded and we calculated labelling indices after 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry. A DNA microarray was used to examine gene expression followed by real-time polymerase chain reaction. Serum IL-6, IL-10, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1beta (MIP-1beta) were measured.


RESULTS
LR in UTI (-/-) mice was delayed at 36 h after hepatectomy, at which time the DNA profile was different. One hundred and fourteen genes were upregulated and 100 genes were downregulated in UTI (-/-) mice at 36 h after hepatectomy among the 21, 977 mRNAs examined. Furthermore, serum IL-6, IL-10, MCP-1 and MIP-1beta levels at 36 h after hepatectomy in the UTI (-/-) mice were significantly higher than in the UTI (+/+) mice.


CONCLUSIONS
UTI appears to important cytokine and chemokine regulation in normal liver regeneration.
Nobuoka
Takayuki
T
Department of Surgery I, Sapporo Medical University Hospital, Sapporo Medical University School of Medicine, Sapporo, Japan.
Mizuguchi
Toru
T
Oshima
Hideki
H
Shibata
Toshihito
T
Kaji
Shinsuke
S
Nagayama
Minoru
M
Meguro
Makoto
M
Mitaka
Toshihiro
T
Hirata
Koichi
K
D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000097:blood; D054407:Chemokine CCL4 / Q000097:blood; D016207:Cytokines / Q000097:blood* / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000172:deficiency* / Q000235:genetics; D006498:Hepatectomy; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D008115:Liver Regeneration / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size; D013997:Time Factors
C491768:Ccl2 protein, mouse; C496535:Ccl4 protein, mouse; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D016207:Cytokines; D006023:Glycoproteins; D015850:Interleukin-6; D016753:Interleukin-10; C028665:urinastatin