Kupffer cell depletion abolishes induction of interleukin-10 and permits sustained overexpression of tumor necrosis factor alpha messenger RNA in the regenerating rat liver

✍ Scribed by R M Rai; S Loffreda; C L Karp; S Yang; H Lin; A M Diehl

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 599 KB
• Volume: 25
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510250417

✦ Synopsis

that synchronize the regenerative response to liver injury Tumor necrosis factor a (TNF), initiates a cytokine and implies that hepatocytes and liver nonparenchymal cells cascade that promotes hepatocyte proliferation after are both the sources of, and the targets for, various growth-70% partial hepatectomy (PH) but the mechanisms reguregulatory cytokines. Thus, to understand how liver regenerlating TNF production after PH are unknown. We preation is regulated, it is critical to delineate the cytokine netviously reported that gadolinium chloride (GdCl), an works that modify the phenotypes of liver cells during this agent that depletes the liver of phagocytically active growth response.

Kupffer cells, enhances hepatic expression of TNF mes-

Several lines of evidence suggest that tumor necrosis factor senger RNA (mRNA) and promotes liver regeneration (TNF) a, is likely to be a key component of the paracrine after subsequent PH. This suggests that GdCl interferes network that promotes hepatocyte proliferation during liver with Kupffer cell mechanisms that normally constrain TNF production after PH. To evaluate this, the pre-and regeneration. The possibility that TNF may play a hepatopost-PH expression of TNF, TNF-inducible cytokines (introphic role is somewhat counterintutitive, given its wellterleukin [IL]-1, IL-6) and cytokines (transforming documented cytotoxic effects in other settings. 2 However, this growth factor [TGF] b 1 and IL-10) that down-regulate theory is supported by data which show that liver DNA syn- TNF were compared in controls and GdCl-treated rats. thesis and hepatocyte mitoses increase in healthy adult rats In controls, TNF, IL-1, IL-6, and IL-10 increase within 3 after intravenous administration of human recombinant hours after PH, whereas TGF-b 1 is induced much later TNF 3 and evidence that pretreatment of rats with neutraliz-(ú24 hours after PH). GdCl causes sustained overexing antibodies to TNF 4 or soluble TNF receptors (Rai RM, et pression of TNF mRNA and transient overexpression of al., Unpublished data, May 1996) inhibits hepatocyte DNA circulating TNF protein after PH; both TNF-inducible synthesis after PH. To date, the mechanisms which control cytokines are also relatively overexpressed. Cytokines TNF production during liver regeneration have not been that down-regulate TNF are effected differentially by characterized.

GdCl. Regenerative induction of IL-10 is abolished but

Isolated Kupffer cells are known to produce TNF when TGF-b 1 induction is unaltered. Because IL-10 is known to stimulated by lipopolysaccharide 5 and are generally preshorten the half-life of TNF mRNA, these results suggest sumed to be an important source of hepatic TNF during an that Kupffer cell production of IL-10 is an important inflammatory response. 6 Thus, we were surprised to discover mechanism that down-regulates TNF production during that gadolinium chloride (GdCl), an agent that depletes the liver regeneration. (HEPATOLOGY 1997;25:889-895.) liver of phagocytically active Kupffer cells, 7 increases hepatic levels of TNF messenger RNA (mRNA). 8 These studies also revealed that GdCl-pretreatment enhances PH-induction of Partial (70%) hepatectomy (PH) evokes a dramatic regenerthe TNF-inducible cytokine, interleukin-6 (IL-6) and ampliative response in the remnant liver. Virtually all remaining fies the hepatocyte proliferative response to PH. 8 Taken tohepatocytes replicate at least once; nonparenchymal cells gether, our previous results suggest that PH evokes a TNFproliferate to reconstitute vascular and biliary conduits; and matrix production is induced to provide the scaffolding neces-initiated cascade which promotes liver regeneration. GdCl sary for regrowth. In rodents, the resected liver mass is repretreatment apparently interferes with Kupffer cell mechastored within about a week and then liver cells promptly nisms that normally restrict TNF production and, thus, amrevert to their prehepatectomy phenotypes. 1 To maintain viplifies TNF-inducible events after PH. tal tissue-specific functions and ensure successful reconstitu-

The purpose of the present study was to identify mechation of organ architecture during liver regeneration, the nisms which may regulate hepatic production of TNF and growth responses of various liver cell populations must be TNF-inducible cytokines after PH. Others have shown that coordinated. This suggests that liver cells exchange signals Kupffer cells produce two cytokines, transforming growth factor b 1 (TGF-b 1 ) and interleukin-10 (IL-10), that inhibit TNF synthesis in other settings. 9,10 Thus, hepatic expression of these cytokines were compared in GdCl-treated and control Abbreviations: PH, partial hepatectomy; TNF, tumor necrosis factor; GdCl, gadolinium rats to evaluate the possibility that one or both may regulate chloride; mRNA, messenger RNA; IL, interleukin; TGF-b1, transforming growth factor b1;

production of TNF by the regenerating liver. Our results

RT-PCR, reverse-transcription polymerase chain reaction; HE, hematoxylin-eosin.