ROLE OF LIPOPOLYSACCHARIDE (LPS), INTERLEUKIN-1, INTERLEUKIN-6, TUMOR-NECROSIS-FACTOR, AND DEXAMETHASONE IN REGULATION OF LPS-BINDING PROTEIN EXPRESSION IN NORMAL HEPATOCYTES AND HEPATOCYTES FROM LPS-TREATED RATS
Yh. Wan et al., ROLE OF LIPOPOLYSACCHARIDE (LPS), INTERLEUKIN-1, INTERLEUKIN-6, TUMOR-NECROSIS-FACTOR, AND DEXAMETHASONE IN REGULATION OF LPS-BINDING PROTEIN EXPRESSION IN NORMAL HEPATOCYTES AND HEPATOCYTES FROM LPS-TREATED RATS, Infection and immunity, 63(7), 1995, pp. 2435-2442
Lipopolysaccharide (LPS)-binding protein (LBP) has been reported to be
an acute-phase protein. LBP binds to LPS with a high affinity; LPS-LB
P complexes then interact with the receptor CD14, resulting in increas
ed expression of LPS-inducible genes, Hepatocytes represent a major so
urce of LBP, but little is known about the regulation of rodent hepato
cyte LBP synthesis. In these studies, undertaken to characterize hepat
ocyte LBP expression, we show that greater-than-20-fold increases in L
BP mRNA levels in hepatocytes occurred following injection of LPS or t
urpentine in rats. In primary cultures of rat hepatocytes, the additio
n of interleukin-6 (IL-6) and LPS led to 4.5- and 3.2-fold stimulation
in LBP mRNA levels, respectively. The induction of LBP by IL-6 or LPS
was attenuated by dexamethasone. In contrast to IL-6 and LPS, in the
presence of 10(-6) M dexamethasone, IL-1 and tumor necrosis factor (TN
F) led to maximal LBP mRNA induction levels, 4.7- and 3.8-fold, respec
tively, suggesting that IL-6 and LPS stimulate LBP expression by mecha
nisms different from those of IL-1 and TNF. Similar induction levels o
f LBP mRNA were seen in rat H35 hepatoma cells for all four stimuli, a
nd dexamethasone inhibited these responses. Dexamethasone alone increa
sed the spontaneous induction in primary hepatocytes at early time poi
nts but suppressed induction at later time points. Furthermore, hepato
cytes from rats treated with LPS in vivo exhibited a > 10-fold increas
e in mRNA expression in response to LPS and enhanced responses to TNF
and IL-1. As with the normal hepatocytes, dexamethasone inhibited the
LPS-dependent induction in the LPS-treated rat hepatocytes. These data
suggest that LBP synthesis by hepatocytes is under the control of LPS
, IL-1, TNF, IL-6, and glucocorticoids and that the LPS treatment prim
es hepatocytes for subsequent responses to LPS, TNF, and IL-1 for LBP
synthesis.