Nonparenchymal cells from regenerating rat liver generate interleukin-1α and -1β: A mechanism of negative regulation of hepatocyte proliferation

✍ Scribed by R Boulton; A Woodman; D Calnan; C Selden; F Tam; H Hodgson

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 337 KB
• Volume: 26
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510260107

✦ Synopsis

role suppressing hepatocyte proliferation and terminating the Following experimental partial hepatectomy of 70% in the surge of DNA synthesis induced after partial hepatectomy. rat, there is a semisynchronized surge of hepatocyte prolifera-(HEPATOLOGY 1997;26:49-58.) tion that ceases after 48 to 72 hours. Little is known about the determinants governing the termination of the proliferative phase, although transforming growth factor (TGF) b has been

The majority of hepatocytes in the adult liver are quiescent implicated as an important inhibitor of hepatocyte replication with respect to proliferation. In the rat, only 0.1% of hepatoin this model. We previously reported an additional noncyte nuclei are engaged in replicative DNA synthesis, and TGF-b inhibitor in medium conditioned by nonparenchymal the mitotic rate is 1 in 10,000; 1 figures for human liver are cells isolated from regenerating liver (CM-NPC-Reg) between similar. Adult hepatocytes remain capable of proliferation, 24 and 48 hours after partial hepatectomy, but it was not and, after injury, there is a prompt regenerative response that found in medium conditioned by nonparenchymal cells from recruits mature hepatocytes into the cell cycle. In the rat unoperated control liver. CM-NPC-Reg suppressed replicative after partial hepatectomy of 70%, cells enter the S phase DNA synthesis of primary rat hepatocytes in response to hepawithin 12 to 15 hours, and up to 40% of hepatocytes are in tocyte growth factor (HGF), epidermal growth factor (EGF),

the S phase at the peak of DNA synthesis 24 hours after or TGF-a as assessed by 3 H-thymidine incorporation. We now resection. 2 At 30 hours' post-resection, there is a synchropresent evidence that interleukin (IL)-1 is the major inhibitor nous wave of hepatocyte mitosis with a histological mitotic of hepatocyte DNA synthesis present in CM-NPC-Reg. IL-1 index of the order of 30%. Hepatocytes may undergo more receptor antagonist abrogated the inhibition, as did antibodies than one round of replication, until the liver regains its forto rat IL-1a and -b; a combination of both antibodies was mer size-typically 7 to 10 days after resection in the rat required, implicating both IL-1a and IL-1b as active constitmodel-when the process terminates. The determinants of uents in CM-NPC-Reg. To investigate in vivo changes in IL-1 hepatocyte proliferation during liver regeneration are highly expression, we assessed expression of IL-1a messenger RNA complex, and different mechanisms operate during the initia-(mRNA) in whole rat liver following partial hepatectomy; tion of DNA synthesis and during the termination of the mRNA was down-regulated at 10 hours in the pre-replicative proliferative surge. Initiating processes within the liver inphase of liver regeneration and up-regulated at 24 hours and clude: 1) disruption of the extracellular matrix, which both 48 hours when proliferation is waning. Rat hepatocytes isorenders hepatocytes more sensitive to growth factors and lated from liver 24 hours after partial hepatectomy showed liberates matrix-sequestered hepatocyte mitogens such as heincreased sensitivity to the inhibitory action of IL-1. Exogepatocyte growth factor (HGF), heparin-binding epidermal nous IL-1b, administered parenterally to a group of rats at 0 growth factor (EGF), and acidic fibroblast growth factor; 3 2) and 12 hours after partial hepatectomy significantly reduced activation of enzymes that liberate active fragments of growth the incorporation of the thymidine analogue, bromodeoxyurifactors (e.g., plasminogen cleavage of HGF); 4 and 3) endine (BrdU), into hepatocytes at 18 hours. These data indicate hanced synthesis of autocrine (transforming growth factor that nonparenchymal cells isolated from regenerating rat liver

[TGF] a) and paracrine (HGF) hepatocyte mitogens. 5,6 In elaborate IL-1, and support the hypothesis that IL-1 plays a addition, neural and systemic influences are recruited-noradrenaline, 7 insulin, and glucagon acting as co-mitogens, 8 and EGF from the submandibular gland, 9 have all been

Abbreviations: HGF, hepatocyte growth factor; EGF, epidermal growth factor; TGF, shown to amplify or sustain the regenerative response. transforming growth factor; CM-NPC-Reg, conditioned medium from nonparenchymal In contrast, the mechanisms terminating the surge of DNA cells isolated from regenerating liver; CM-NPC-Con, conditioned medium from nonparenchymal cells from control liver; IL, interleukin; mRNA, messenger RNA; MTT, 3-synthesis have been less investigated until recently. The ter-[4,5-dimethylthiazol-2-yl]-2,5,-diphenyl tetrazolium bromide; PBS, phosphate-bufmination of proliferation and the restoration of normal liver fered saline; BrdU, bromodeoxyuridine; IL-1ra, interleukin-1 receptor antagonist. cell mass have been variously attributed to the temporary fall From the Department of Medicine, Royal Postgraduate Medical School, Hammerin concentration of a negative regulatory chalone normally