Kupffer cell depletion by CI2MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy.
BACKGROUND
Although Kupffer cells (KCs) are capable of producing important growth-stimulating cytokines, their role in liver regeneration following partial hepatectomy (PH) remains poorly understood.


METHODS
In the present study liver regeneration was studied after KC-depletion by intravenous administration of liposome-encapsulated dichloromethylene-diphosphonate (C12MDP), a method known to physically eliminate KCs. Furthermore, splenectomy was performed one week prior to PH to exclude the effect of C12MDP-liposomes on macrophage populations in the spleen.


RESULTS
KC-depletion was confirmed in cryostat liver sections stained with the monoclonal antibody ED2, a marker for resident tissue macrophages. Forty-eight hours after PH, the cumulative hepatocyte DNA synthesis, as determined in liver sections by the hepatocyte bromodeoxyuridine labeling index, was significantly decreased in KC-depleted rats when compared to control-rats. The weight of the remnant liver, expressed as a percentage of the initial liver weight, was significantly less at 96 h after PH in KC-depleted rats. KC-depletion abolished the hepatic interleukin-6 (IL-6) and interleukin-10 (IL-10) mRNA synthesis and decreased hepatic expression of tumor necrosis factor-alpha (TNF-alpha), hepatocyte growth factor (HGF) and transforming growth factor-beta1(TGF-beta1) mRNA after PH, as was assessed by reverse-transcriptase polymerase chain reaction (RT-PCR). Moreover, at 4 h after PH the systemic release of IL-6 was significantly decreased in KC-depleted rats.


CONCLUSIONS
We conclude that KCs are important for hepatocyte regeneration after PH. Delayed liver regeneration in KC-depleted rats can be explained, at least in part, by an imbalanced hepatic cytokine expression, thereby suppressing important growth-stimulating cytokines.
Meijer
C
C
Department of Surgery, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Wiezer
M J
MJ
Diehl
A M
AM
Schouten
H J
HJ
Schouten
H J
HJ
Meijer
S
S
van Rooijen
N
N
van Lambalgen
A A
AA
Dijkstra
C D
CD
van Leeuwen
P A
PA
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D004002:Clodronic Acid / Q000633:toxicity; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004337:Drug Carriers; D006498:Hepatectomy; D007124:Immunoenzyme Techniques; D007728:Kupffer Cells / Q000187:drug effects / Q000502:physiology*; D008081:Liposomes; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D012313:RNA / Q000032:analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013047:Specific Pathogen-Free Organisms
D016207:Cytokines; D004337:Drug Carriers; D008081:Liposomes; D012333:RNA, Messenger; D004002:Clodronic Acid; D012313:RNA; D004247:DNA; D001973:Bromodeoxyuridine