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.