Mitosis and apoptosis in the liver of interleukin-6-deficient mice after partial hepatectomy

Citation
T. Sakamoto et al., Mitosis and apoptosis in the liver of interleukin-6-deficient mice after partial hepatectomy, HEPATOLOGY, 29(2), 1999, pp. 403-411
Citations number
37
Categorie Soggetti
Gastroenerology and Hepatology","da verificare
Journal title
HEPATOLOGY
ISSN journal
02709139 → ACNP
Volume
29
Issue
2
Year of publication
1999
Pages
403 - 411
Database
ISI
SICI code
0270-9139(199902)29:2<403:MAAITL>2.0.ZU;2-0
Abstract
Recently, it was shown that hepatocyte DNA synthesis after partial hepatect omy (PH) is impaired in interleukin-6-deficient (IL-6(-/-)) mice, which res ults in significantly delayed, but eventual, recovery of normal liver weigh t, compared with the IL-6(+/+) controls. Four possible compensatory mechani sms might explain this phenomenon: 1) hepatocyte hypertrophy; 2) activation of the oval cell compartment and subsequent maturation to hepatocytes; 3) non-oval biliary epithelial cell (BEC) proliferation; and/or 4) differentia l rates of apoptotic cell death in the regenerating liver. These hypotheses were tested by subjecting IL-6(-/-) and IL-6(+/+) mice to PH and determini ng sequential liver weight, histology, hepatocyte and BEC 5'-bromo-2'-deoxy uridine (BrdU) labeling, liver DNA content, a-fetoprotein (AFP) mRNA produc tion, and apoptosis at several time points after PH. Consistent with previo us studies, we show that the absence of IL-6 significantly impairs hepatocy te DNA synthesis and delays liver weight recovery after PH, but the defect observed in this study is less severe than that previously resorted, and no excess mortality, massive necrosis on histology, nor differences in liver injury test are seen. interestingly, the IL-6-/- mice show more hepatocyte BrdU pulse labeling than the IL-6(+/+) controls at 24 hours, but less at 36 , 48, and 60 hours. Continuous BrdU infusion up to 60 hours after PH showed a cumulative hepatocyte labeling index of 79.5% in IL-6(+/+) mice and 70.8 % in IL-6(-/-) mice, respectively (P <.03). However, despite a lower labeli ng index and significantly delayed weight recovery, hepatic mass was equall y restored in the two groups by 96 hours. There was no evidence of oval cel l proliferation in the IL-6(-/-) mice, as determined by routine histology a nd AFP mRNA analysis, and non-oval BEC proliferation was also slightly impa ired in the IL-6(-/-) mice compared with the IL-6(+/+) mice. In addition, l iver DNA content per gram of liver showed an increase compared with normal at 60 hours in both groups, but by 96 hours, there was no difference betwee n the two groups. Thus, neither oval cell nor BEC proliferation, nor hepato cyte hypertrophy, could account for the eventual equivalent weight recovery . There was, however, a difference between the two groups in the rate of ap optosis, In normal livers of both IL-6(-/-) and IL-6(+/+) mice, apoptotic c ells were uncommon, and even fewer such cells were detected at 24, 36, and 48 hours after PH. Between 60 and 96 hours after PH, a wave of apoptosis sp read through the livers of both groups. The number of apoptotic cells was d irectly proportional to the magnitude of hepatocyte BrdU labeling and liver DNA content after PH, and the difference between the nadir of apoptosis at 24 hours and the peak at 96 hours was greater for the IL-6(+/+) mice. In a ddition, a direct comparison between the two groups at 96 hours showed that hepatocyte apoptosis was significantly lower in the IL-6(-/-) versus the I L-6(+/+) mice (P <.02), Treatment of the IL-6(-/-) mice with rIL-6 complete ly reversed the hepatocyte proliferation defect and increased the subsequen t level of total apoptotic bodies. The fine control of liver weight recover y during regeneration after PH is a complex process that involves both mito sis and apoptosis. IL-6 affects this process by recruiting, and possibly sy nchronizing, the entry of hepatocytes into cell cycling, which quickly rest ores liver mass. However, this robust response generates superfluous hepatocytes, which are eliminated via apoptosis, similar to many other processes involving organ g rowth.