Kupffer cell depletion abolishes induction of interleukin-10 and permits sustained overexpression of tumor necrosis factor alpha messenger RNA in the regenerating rat liver.
Tumor necrosis factor alpha (TNF), initiates a cytokine cascade that promotes hepatocyte proliferation after 70% partial hepatectomy (PH) but the mechanisms regulating TNF production after PH are unknown. We previously reported that gadolinium chloride (GdCl), an agent that depletes the liver of phagocytically active Kupffer cells, enhances hepatic expression of TNF messenger RNA (mRNA) and promotes liver regeneration after subsequent PH. This suggests that GdCl interferes with Kupffer cell mechanisms that normally constrain TNF production after PH. To evaluate this, the pre- and post-PH expression of TNF, TNF-inducible cytokines (interleukin [IL]-1, IL-6) and cytokines (transforming growth factor [TGF] beta 1 and IL-10) that down-regulate TNF were compared in controls and GdCl-treated rats. In controls, TNF, IL-1, IL-6, and IL-10 increase within 3 hours after PH, whereas TGF-beta 1 is induced much later (> 24 hours after PH). GdCl causes sustained overexpression of TNF mRNA and transient overexpression of circulating TNF protein after PH; both TNF-inducible cytokines are also relatively overexpressed. Cytokines that down-regulate TNF are effected differentially by GdCl. Regenerative induction of IL-10 is abolished but TGF-beta 1 induction is unaltered. Because IL-10 is known to shorten the half-life of TNF mRNA, these results suggest that Kupffer cell production of IL-10 is an important mechanism that down-regulates TNF production during liver regeneration.
Rai
R M
RM
Department of Medicine, Johns Hopkins University and School of Medicine, Baltimore, MD 21205-2195, USA.
Loffreda
S
S
Karp
C L
CL
Yang
S Q
SQ
Lin
H Z
HZ
Diehl
A M
AM
D000818:Animals; D001483:Base Sequence; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005682:Gadolinium / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006498:Hepatectomy; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D007728:Kupffer Cells / Q000187:drug effects / Q000502:physiology*; D008115:Liver Regeneration / Q000235:genetics* / Q000502:physiology*; D008297:Male; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D016207:Cytokines; D017931:DNA Primers; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D005682:Gadolinium; C038958:gadolinium chloride