Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
1 To whom correspondence should be addressed at Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160. Fax: (913) 588-7501. E-mail: cklaasse{at}kumc.edu.
Received December 21, 2003; accepted August 28, 2004
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ABSTRACT |
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Key Words: Oatp4; LPS; TNF; IL-1; IL-6; iNOS.
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INTRODUCTION |
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Extracellular LPS signaling is known to be mediated by TLR4, leading to a marked release of cytokines and other mediators. Kupffer cells, the resident macrophages in liver, are activated by LPS and/or cytokines to produce inflammatory cytokines as well as inducible nitric oxide synthase (iNOS). Binding of these cytokines to their receptors at the sinusoidal membrane of hepatocytes triggers complex signaling pathways, leading to alterations in liver gene expression, predominantly at the transcriptional level (Andus et al., 1991; Moshage, 1997
). For example, LPS-induced cholestasis is thought to be due to a rapid down-regulation of transport proteins, such as the sinusoidal Na+/taurocholate cotransporting polypeptide (Ntcp) (Bolder et al., 1997
; Green et al., 1996
; Moseley et al., 1996
) and canalicular multidrug resistance associated protein 2 (Mrp2), as well as the bile salt export pump (Bsep) (Roelofsen et al., 1997
; Trauner et al., 1997
; Vos et al., 1998
).
Several lines of evidence suggest that LPS-induced cholestasis and down-regulation of hepatic transporters are mediated by cytokines. For example, (1) TNF- antibodies prevent the reductions in basal bile flow and bile acid excretion that occur after LPS administration (Whiting et al., 1995
), implicating TNF-
involvement in LPS-mediated cholestasis. (2) Down-regulation of sinusoidal Ntcp and canalicular Mrp2 at both mRNA and protein levels is additionally observed after administration of TNF-
or IL-1ß (Green et al., 1996
; Moseley et al., 1996
). (3) Pretreatment with dexamethasone, which blocks LPS-mediated release of TNF-
and IL-1, prevents reduction of Mrp2 activity after LPS treatment (Kubitz et al., 1999
; Roelofsen et al., 1995
). (4) Administration of LPS or IL-6 to mice reduces Mdr1 and Mdr2 mRNA and protein levels (Hartmann et al., 2001
). (5) Both LPS and IL-6 administration decrease Oatp1, Oatp2, Mrp2, and Bsep mRNA levels (Hartmann et al., 2002
). Collectively, these studies suggest that the effect of LPS on hepatic transporter expression is mediated by cytokines. In fact, several cytokines (TNF-
, IL-1ß, and IL-6) have been shown to alter the pattern of hepatic protein synthesis and intermediary metabolism of hepatocytes both in vitro and in vivo (Argiles and Lopez-Soriano, 1990
). Therefore, it is reasonable to hypothesize that TNF-
, IL-1ß, and IL-6 are important mediators of the LPS-induced down-regulation of the hepatic uptake transporter Oatp4.
Among the aforementioned cytokines, TNF- is a primary mediator of the systemic effects of LPS (Beutler et al., 1985
; Cerami and Beutler, 1988
). Protection against LPS lethality can be conferred by passive immunization with anti-TNF antiserum, or with soluble recombinant human TNF receptor-immunoglobulin chimeric proteins (Beutler et al., 1985
). Therefore, TNF appears to be a major factor in LPS toxicity (Beutler and Cerami, 1988
). TNF-
binds to two forms of receptors, type I (55 kD) and type II (75 kD). Both isoforms are present in hepatocytes with a low basal level of expression. The expression of TNF receptors is increased during acute or chronic liver inflammation (Volpes et al., 1992
). Most of the known cellular TNF responses are attributed to activation of the 55 kD TNF receptor (TNFRp55). In TNFRp55-deficient mice, TNF signaling is mostly abolished, with no induction of NF-
B by TNF. Moreover, the loss of TNFRp55 function renders mice resistant to lethal doses of LPS (Pfeffer et al., 1993
).
The biologic activity of IL-1ß is mediated via the specific cell-surface receptor, known as type I IL-1 receptor (IL-1RI). IL-1RI is the only known receptor capable of mediating signaling of IL-1 (Sims et al., 1993), whereas the type II IL-1R acts as a nonsignaling decoy receptor, which is shed from the cell surface, thereby preventing IL-1 binding to IL-1RI (Colotta et al., 1994
). Mice homozygous for the IL-1RI targeted mutation are of normal vigor and exhibit no overt phenotype, except that the response to IL-1 is abolished (Glaccum et al., 1997
).
Among these three cytokines, IL-6 is recognized as the most important cytokine modulating the hepatic expression of acute-phase genes (Heinrich et al., 1990). Mice homozygous for the IL-6 targeted mutation are viable and fertile. However, the inflammatory acute-phase response after tissue damage or infection is severely compromised, whereas it is only moderately affected after challenge with LPS (Kopf et al., 1994
).
In addition to cytokines, LPS also increases nitric oxide synthase (NOS). Two forms of NOS are present in liver. Constitutive NOS (cNOS) activity in liver is detectable in Kupffer cells, however, no cNOS is expressed in hepatocytes. Inducible nitric oxide synthase (iNOS) is synthesized de novo upon exposure to LPS and/or cytokines, and produces large amounts of NO over prolonged periods of time (Muriel, 2000). In addition to Kupffer cells, hepatocytes and stellate cells are prompted to express a marked increase in iNOS activity, once exposed to effective stimuli (Laubach et al., 1995
). Mice homozygous for the iNOS targeted mutation are viable and fertile. The mutant mice exhibit no significant survival advantage over wild-type mice after LPS administration (Laubach et al., 1995
). Moreover, mice lacking iNOS are indistinguishable from wild-type mice in appearance and histology.
The purpose of the present study was to determine the role of individual endogenous cytokines or iNOS-produced NO in the LPS-induced down-regulation of Oatp4. Therefore, Oatp4 mRNA levels were determined at various times after LPS administration to wild-type mice, as well as mice homozygous for targeted mutations of TNFRp55, IL-1RI, IL-6, or iNOS. In addition, the effect of recombinant murine TNF-, IL-1ß, and IL-6 on the activity of the mouse Oatp4 promoter (4.8 kb to +30) was examined in mouse hepatoma cells.
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MATERIALS AND METHODS |
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RNA isolation. Total RNA was isolated from liver using RNAzol B reagent (Tel-Test Inc., Friendswood, TX), according to the manufacturer's protocol. The concentration of total RNA in each sample was quantified spectrophotometrically at 260 nm. The integrity of each RNA sample was evaluated by formaldehyde-agarose gel electrophoresis before analysis.
Branched DNA (bDNA) assays. Oatp4 mRNA levels in liver were determined by the branched DNA signal amplification assay (QuantiGene® bDNA Signal Amplification Kit, Bayer Diagnostics, East Walpole, MA) (Hartley and Klaassen, 2000). Mouse Oatp4 gene sequence was accessed from GenBank (Accession number AB031959). A multiple oligonucleotide probe set (capture, label, and blocker probes) specific to the mouse Oatp4 transcript (Table 1) was designed using ProbeDesigner software, version 1.0 (Bayer Corp. Diagnostics Div., Tarrytown, NY). Each probe developed in ProbeDesigner was submitted to the National Center for Biotechnology Information for nucleotide comparison by the basic local alignment search tool (NCBI, Bethesda, MD), to ensure minimal cross-reactivity with other known mouse sequences and expressed sequence tags. Any oligonucleotide with a high degree of similarity (>80%) to other mouse gene transcripts was eliminated from the design. Probes were designed with a melting temperature of approximately 63°C, enabling hybridization conditions to be held constant (i.e., 53°C) during each hybridization step. All probes were synthesized by Operon Technologies (Palo Alto, CA). Total RNA (1 µg/µl) was added to each well (10 µl/well) of a 96-well plate containing 50 µl of capture hybridization buffer and 50 µl of diluted probe set, and allowed to hybridize to the probe set overnight at 53°C. Subsequent hybridization and wash steps were carried out according to the manufacturer's protocol. Luminescence from 96-well plates was analyzed with a Quantiplex 320 bDNA luminometer interfaced with Quantiplex data management software, version 5.02 (Bayer Diagnostics). Luminescence for each well was reported as relative light units (RLU) per 10 µg of total RNA.
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Cell culture and transient transfections. Mouse hepatoma HEPA1-6 cells were purchased from American Type Culture Collection (ATCC) (Manassas, VA). Cells were maintained in Dubecco's Modified Eagle Medium (ATCC) supplemented with 10% fetal bovine serum (ATCC). Cells were seeded at 8590% density in 24-well plates. To normalize for transfection efficiency, the phRL-TK plasmid (Promega Corporation, Madison, WI) encoding Renilla luciferase, under the control of a thymidine kinase promoter, was cotransfected with the p4.8kbOatp4-Luc. Transient transfections were performed with 1 µg of the p4.8kbOatp4-Luc plasmid, 1 ng of the internal control phRL-TK plasmid, and 3 µl of LipofectAMINE 2000 (Invitrogen Corporation, Carlsbad, CA) per well. Medium was replaced with culture medium 5 h after transfection. After overnight incubation, medium was switched to serum-free DMEM and incubated for another 16 to 24 h. Cells were then treated with murine recombinant TNF-, IL-1ß, and IL-6 obtained from R&D Systems (Minneapolis, MN) in serum-free medium. The cells were harvested 424 h later for reporter assays (Promega Corporation, Madison, WI). Each treatment was evaluated in triplicate within each transfection, and transfections were performed a minimum of three times.
Statistical analysis. Differences between control and treatment were analyzed by ANOVA, followed by Duncan's multiple range post-hoc test. Differences between groups at each time point were analyzed by the Student's t-test. Statistical significance was set at p < 0.05.
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RESULTS |
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DISCUSSION |
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During the acute-phase response, the levels of certain proteins (e.g., C-reactive protein, serum amyloid A) increase (positive acute-phase proteins), whereas the levels of other proteins (e.g., albumin, transferrin) decrease (negative acute-phase proteins). In addition, detoxification of xenobiotics by some cytochromes P450 (CYPs) and biliary excretion of endo- and xenobiotics by transporters are known to be influenced by cytokines in a negative manner. It has been shown that IL-6, IL-1, and TNF- mediate the transcriptional regulation of negative acute-phase proteins. For example, IL-6 down-regulates the hepatic albumin gene through the transcription factor C/EBP (Descombes and Schibler, 1991
; Trautwein et al., 1996
). The hepatic nuclear binding activity to the putative C/EBP binding site of the mouse Oatp4 promoter is markedly decreased after LPS administration (in preparation). Thus, the response of Oatp4 to LPS treatment is similar to that of negative acute-phase proteins. Therefore, the LPS-induced down-regulation of hepatic transporters should be considered as a negative acute-phase response. The liver is the major organ for LPS toxicity. Studies on effects of LPS on liver gene expression may provide understanding how the liver maintains homeostasis in response to microbial stimuli.
Targeted disruption of various cytokines or their receptors makes it possible to examine whether endogenous cytokines are required for the LPS-induced down-regulation of Oatp4 mRNA. Therefore, mice homozygous for the targeted mutation of TNFRp55, IL-1RI, or IL-6 were employed to study the effect of LPS on Oatp4 mRNA, in order to completely remove the responses produced by endogenous TNF, IL-1, or IL-6, respectively. As shown in Figures 13, absence of the TNFRp55, IL-1RI, or IL-6 did not prevent the LPS-induced decrease in Oatp4 mRNA levels as observed in wild-type mice. These results suggest that the decrease in Oatp4 mRNA levels produced by LPS is independent of TNF-
, IL-1ß, or IL-6.
LPS is not only an inducer of cytokines, but also a potent activator of iNOS in liver, leading to an increase in production of NO (Laubach et al., 1995). The role of endogenous NO produced by iNOS in the LPS-induced down-regulation of Oatp4 mRNA was examined using iNOS-null mice. Targeted deletion of iNOS did not prevent the LPS-induced decrease in Oatp4 mRNA levels (Fig. 4), suggesting that iNOS is not required for the LPS-induced down-regulation of Oatp4.
Because the down-regulation of Oatp4 mRNA in mice does not appear to be due to a single cytokine, an in vitro system was selected to determine whether a combination of cytokines would decrease mouse Oatp4 promoter activity. Mouse hepatoma HEPA1-6 cells are widely used as a model to elucidate gene expression and functions in liver. For example, mouse hepatoma HEPA1-6 cells are responsive to cytokines TNF-, IL-1ß, and IL-6 for the induction of cell surface receptors of hepatocyte growth factor (HGF), as well as HGF-like protein (Chen et al., 1997
). Similar to observations in vivo, Mrp2 mRNA levels are significantly diminished in IL-1ß- and IL-6-treated HEPA1-6 cells (Hartmann et al., 2002
). Moreover, the transport activity of Mrp2 is reduced in IL-6-, IL-1ß-, and TNF-
-treated HEPA1-6 cells. Taken together, these studies indicate that mouse hepatoma HEPA1-6 cells are responsive to TNF-
, IL-1ß, and IL-6 in both positive and negative regulation of liver gene expression.
In the present study, mouse hepatoma HEPA1-6 cells were transiently transfected with a reporter construct containing 4.8-kb Oatp4 promoter before treatment with various concentrations of recombinant murine TNF-, IL-1ß, and IL-6. The cytokine concentrations in the medium were higher than serum concentrations of TNF-
(3.4 ng/ml), IL-1ß (381 pg/ml), and IL-6 (23.3 ng/ml) after administration of LPS (5 mg/kg, ip) to mice, which produces an 80% decrease in Oatp4 mRNA levels (Li et al., 2002a
). The middle concentration of cytokines used in the present in vitro studies is the high concentration usually used with hepatoma cells. In addition to exposing cells to only one cytokine, two different combinations of cytokine concentrations were also used in the present in vitro studies. One combination consisted of the low concentrations of TNF-
, IL-1ß, and IL-6 used individually, and the other combination consisted of the middle concentrations of the three cytokines. Thus, the cytokine concentrations used in the in vitro studies were similar to or higher than those in the in vivo study. However, the mouse Oatp4 promoter activity was not decreased after treatment of mouse hepatoma cells with murine TNF-
, IL-1ß, or IL-6 at any examined concentration of the cytokine, either individually or in combination (Fig. 5). This in vitro observation is consistent with the observations in vivo described above (Figs. 1
3).
The present data indicate that the decrease in Oatp4 mRNA levels by LPS treatment is not due to TNF-, IL-1ß, and IL-6. Previously mentioned studies suggest that the mechanism of LPS-induced down-regulation of hepatic transporters might be due to cytokines stimulated after LPS administration (see introduction). However, other studies suggest that the LPS-induced decrease in gene expression is not due to cytokines. For example, LPS has been shown to down-regulate CYP1A, 2B, and 3A in mice (Warren et al., 1999
). A decrease in CYPs is also observed when exogenous TNF-
is administered to mice (Chen et al., 1992
; Nadin et al., 1995
; Pous et al., 1990
). However, mice deficient in TNF receptors (p55/p75) exhibit a similar decrease in protein levels of the three cytochromes P450 as do wild-type mice (Warren et al., 1999
). Therefore, TNF-
is not the mediator in the LPS-induced down-regulation of the CYPs. In addition, LPS is known to up-regulate two concentrative nucleoside transporters CNT1 and CNT2 (Soler et al., 2001
). Moreover, TNF-
administration mimics the LPS-induced up-regulation of CNT1 and CNT2. However, macrophages isolated from mice deficient in TNFRp55 exhibit a similar up-regulation of CNT1 and CNT2 after LPS treatment. Therefore, TNF-
is not required for the LPS-induced up-regulation of CNT1 and CNT2. Thus, Oatp4 is not the only gene in the category of drug metabolism and transport that is not regulated by TNF-
.
In summary, LPS produced a similar decrease in Oatp4 mRNA levels in mice lacking TNFRp55, IL-1RI, IL-6, or iNOS, compared with wild-type mice in vivo. Moreover, neither individual nor combined treatment of mouse hepatoma cells with murine TNF-, IL-1ß, and IL-6 suppressed mouse Oatp4 promoter activity. Therefore, LPS appears to down-regulate Oatp4 mRNA independently of TNF-
, IL-1ß, IL-6, or iNOS.
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NOTES |
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