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Inhibition by Interleukin-1ß and Tumor Necrosis Factor- of the Insulin-Like Growth Factor I Messenger Ribonucleic Acid Response to Growth Hormone in Rat Hepatocyte Primary Culture¹

Unité de Diabétologie et Nutrition, School of Medicine, The University of Louvain, B-1200 Brussels, Belgium

Address all correspondence and requests for reprints to: Jean-Paul Thissen, M.D., Unité de Diabétologie et Nutrition, UCL/DIAB 5474 Avenue Hippocrate, 54, B-1200 Brussels, Belgium. E-mail: thissen{at}diab.ucl.ac.be

	Abstract

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The cytokines are the putative mediators of the catabolic reaction that accompanies infection and trauma. Evidence suggests that their catabolic actions are indirect and potentially mediated through changes in hormonal axis such as the hypothalamo-pituitary-adrenal axis. Insulin-like growth factor I (IGF-I) is a GH-dependent growth factor that regulates the protein metabolism. To determine whether cytokines can directly inhibit the production of IGF-I by the liver, we investigated the regulation of IGF-I gene expression by interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)- (10 ng/ml) in a model of rat primary cultured hepatocytes. Hepatocytes were isolated by liver collagenase perfusion and cultured on Matrigel 48 h before experiments. Each experiment was performed in at least three different animals. In the absence of GH, IL-1ß and TNF- did not affect the IGF-I messenger RNA (mRNA) basal levels, whereas IL-6 increased it by a factor of 2.5 after 24 h (P < 0.05). GH (500 ng/ml) alone stimulated the IGF-I gene expression markedly (5- to 10-fold increase) after 24 h (P < 0.001). IL-1ß, and TNF- to a lesser extent, dramatically inhibited the IGF-I mRNA response to GH (IL-1ß: -82%, P < 0.001 and TNF-: -47%, P < 0.01). The half-maximal inhibition of the IGF-I mRNA response to GH was observed for a concentration of IL-1ß between 0.1 and 1 ng/ml. Moreover, IL-1ß abolished the IL-6-induced IGF-I mRNA response. In contrast, IL-6 did not impair the IGF-I mRNA response to GH. To determine the potential role of the GH receptor (GHR) and the GH-binding protein (GHBP) in this GH resistance, we assessed the GHR and GHBP mRNAs response to these cytokines. GH alone did not affect the GHR/GHBP mRNA levels. IL-1ß markedly decreased the GHR and GHBP mRNA levels (respectively, -68% and -60%, P < 0.05). Neither TNF- nor IL-6 affected the GHR/GHBP gene expression. In conclusion, our results show that IL-1ß, and TNF- to a lesser extent, blunt the IGF-I mRNA response to GH. The resistance to GH induced by IL-1ß might be mediated by a decrease of GH receptors, as suggested by the marked reduction of GHR mRNA. These findings suggest that decreased circulating IGF-I, in response to infection and trauma, may be caused by a direct effect of cytokines at the hepatocyte level.

	Introduction

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CATABOLIC STATES, such as those induced by sepsis and trauma, are characterized by severe muscle wasting and negative nitrogen balance (1). Although several cytokines, in particular interleukin (IL)-1ß and tumor necrosis factor (TNF)-, seem involved in the development of these catabolic states (2, 3), the mechanism of their actions in these situations has not been completely unravelled. Several lines of evidence suggest the role of alterations in the GH-insulin-like growth factor (IGF)-I axis in the development of these catabolic situations. First, IGF-I is a GH-dependent anabolic hormone that stimulates protein synthesis and reduces protein breakdown (4, 5). Second, administration of endotoxin or cytokines (IL-1ß, TNF-) decreases the IGF-I production by liver and other tissues (6, 7, 8). Third, exogenous GH and IGF-I have been reported to improve nitrogen balance in catabolic situations (9, 10).

The mechanisms whereby IL-1ß and TNF- decrease liver IGF-I production have not yet been defined. Indeed, these cytokines can impair the GH-IGF-I axis at several levels. First, cytokines, in particular IL-1ß, have been shown to decrease GH secretion in vivo (11, 12). Second, infusion of IL-1ß and TNF- induces profound anorexia susceptible to decrease circulating IGF-I (13). Third, endotoxin, as well as IL-1ß and TNF-, can stimulate secretion of stress hormones as glucocorticoids (6), and these hormones can, in turn, induce a state of GH resistance (14, 15). Finally, the possibility of a direct effect of cytokines on hepatocyte IGF-I gene expression has never been investigated.

The purpose of the present study was to investigate the direct effect of cytokines on hepatocyte IGF-I gene expression. To address this question, we assessed the regulation by various cytokines of basal and GH-stimulated IGF-I gene expression in primary culture of rat hepatocytes. In addition, the regulation by cytokines of the expression of the GH receptor (GHR) and the GH binding protein (GHBP) gene expression was also determined.

	Materials and Methods

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Animals and materials
Male Wistar rats (Katholieke Universiteit of Leuven, Leuven, Belgium), about 6 weeks old (217 ± 15 g; mean ± SD), were maintained under standardized conditions of light and temperature with free access to animal chow and water. Collagenase (type B) was purchased from Boehringer-Mannheim (Mannheim, Germany). Rat GH (rGH) (NIH B-13, AFP-87401) was a gift from the NIADDK. Insulin, hydrocortisone, ethanolamine, sodium selenite, L-ornithine, L-lactic acid, EGTA, and HEPES were purchased from Sigma Chemical Co. (St. Louis, MO). Plastic dishes manufactured by Nunc and DMEM/Ham’s F-12 medium were purchased from Life Technologies (Roskilde, Denmark and Paisley,Scotland). Medium was prepared by the Tissue Culture Facility of the Ludwig Institute at the International Cellular Pathology Institute (Brussels, Belgium). Recombinant murine IL-1ß, IL-6, and TNF- were purchased through R & D Systems (Abingdon, UK).

Hepatocyte isolation and cell culture
Matrigel was prepared from Engelbreth-Holm-Swarm sarcoma propagated in C57BL/6 female mice and stored at -20 C, as previously described (16). After thawing on ice, 170 µl were evenly spread on 60-mm plastic dishes and allowed to form a gel at 37 C. Hepatocytes were prepared by nonrecirculating collagenase perfusion through the portal vein of rats anesthetized with pentobarbital (60 mg/kg), as previously described (17). An aliquot of the final suspension was diluted with trypan blue (1:3) to count the cells and determine the viability, which was always over 90% with a mean of 95% ± 1%. The purity of the hepatocyte preparations was assessed by an immunocytochemical technique using an antibody raised against vimentin, a marker of nonparenchymatous cells. Using this technique, the percentage of nonparenchymatous cells was 4 ± 1% (mean ± SD, n = 3). Cells were seeded at a density of 1.8 x 10⁶ per dish in 3 ml serum-free DMEM/Ham’s F-12 medium. The medium was supplemented with penicillin/streptomycin (100 U/ml and 100 µg/ml, respectively), hydrocortisone (5 x 10^-8 M), insulin (1.75 x 10^-7 M), L-ornithine (4 x 10^-4 M), L-lactic acid (1.77 x 10^-5 M), selenium (2.5 x 10^-8 M), ethanolamine (1 x 10^-6 M). Cultures were maintained at 37 C in a humidified incubator in an atmosphere containing 5% CO₂. Sixteen hours after the plating, the medium was changed and renewed once. After 48 h of culture, cells were incubated for 24 h in serum-free DMEM/Ham’s F-12 medium supplemented as previously described and containing cytokines and/or rGH at different concentrations, as expressed in the figures. Each value represents a pool of three or four 60-mm plates. Results are presented as mean values of three separate experiments, each performed with a different rat.

Lactate deshydrogenase activity (LDH)
Membrane integrity was assessed by measuring the extracellular LDH activity relative to the total LDH activity (intracellular and extracellular). The LDH activity in cell homogenates and culture supernatants was determined spectrophotometrically (Hitachi, Ibaraki, Japan) with a commercially available kit (Boehringer Mannheim), following the manufacturer’s instructions.

RNA extraction and Northern blot analysis
The cells were washed twice with PBS 1x pH 7.4, collected with guanidine thiocyanate (1 ml/60-mm plate) and stored immediately at -70 C. The four plates representing the same point were pooled at this step. Total hepatocyte RNA was extracted using the guanidine thiocyanate and cesium chloride method (18). The yield of total RNA was 50–60 µg/plate. Each 20-µg sample of total RNA was denatured in formaldehyde-MOPS and subjected to electrophoresis on 1% agarose gels. Homogeneity of RNA loading was assessed by UV transillumination of the gels after staining with ethidium bromide. The RNA was transferred to nylon membranes (Hybond, Amersham, Buckinghamshire, UK) by vacuum blotting (Vacugene, Pharmacia, Uppsala, Sweden). Levels of IGF-I messenger RNA (mRNA) and GHR/GHBP mRNAs were determined by hybridization with a specific riboprobe. A 194-bp AvaII-HinfI complementary DNA (cDNA) rat IGF-I exon 4 fragment (19) was ligated into the plasmid vector Bluescript (Stratagene, La Jolla, CA). This probe includes only coding region for the mature IGF-I peptide. The 951-bp BglII fragment of the rGHR cDNA, subcloned into the vector pT₇T₃, was linearized with BamHl (20). Specific ³²P-labeled RNA antisense probes were generated from linearized plasmids with uridine 5'-[-³²P]triphosphate (Amersham, Arlington Heights, IL; specific activity, 410 Ci/mmol) using the T₃ or T₇ promoter. The mRNA levels were quantified by densitometric scanning of the hybridization signal (LKB Ultroscan XL laser densitometry; LKB, Bromma, Sweden) with the use of a software (Gel Scan, Pharmacia). All size-class IGF-I mRNA transcripts were pooled together. The mRNA levels were normalized by assigning the mRNA levels observed after 48 h culture (control 48 h, or 48-h-old hepatocytes) an arbitrary value of 100%. Blots were reprobed with chicken ß-actin cDNA labeled with ³²P to assess the specificity of the observed changes in IGF-I and GHR/GHBP mRNAs. Data presented are not normalized to ß-actin gene expression.

Statistical analysis
Experimental data are presented as mean ± SEM and analyzed by ANOVA, followed by Newman-Keuls test. Statistical significance was set at P < 0.05.

	Results

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Regulation of IGF-I mRNA
Dose-response curve to GH. In the absence of IL-1ß, GH caused a dose-dependent increase in IGF-I mRNA levels that peaked (9-fold increase) at a concentration of 500 ng/ml, the highest concentration tested [P < 0.001 vs. without (w/o) GH; Fig. 1, A and B]. The IGF-I mRNA induction was half-maximal at GH concentrations between 10 and 50 ng/ml (around 1 nM). In the presence of IL-1ß (10 ng/ml), the GH-induced accumulation of IGF-I mRNA was dramatically suppressed (-80% at 50 ng/ml, P < 0.001; -88% at 100 ng/ml, P < 0.001; and -83% at 500 ng/ml, P < 0.001). Even in the presence of a maximal dose of GH (500 ng/ml), the IGF-I mRNA levels did not rise significantly when the cells were incubated with IL-1ß.

View larger version (41K): [in this window] [in a new window]   Figure 1. A, Northern blot analysis of IGF-I mRNA response to increasing concentrations of GH in presence or absence of IL-1ß. Forty-eight-hour-old hepatocytes were incubated with increasing concentrations of rGH (from 1–500 ng/ml) in presence or absence of IL-1ß (10 ng/ml). Northern blot analysis was performed as indicated in Materials and Methods. IGF-I mRNA levels at the beginning of the experimental period (control 48 h) were used as control. B, Relative abundance of IGF-I mRNA in hepatocytes incubated with increasing concentrations of rGH (from 1–500 ng/ml) in presence [IL-1ß (+)] or absence [IL-1ß (-)] of IL-1ß (10 ng/ml). Each value represents the mean ± SEM of three separate experiments. ***, P < 0.001 vs. the corresponding group w/o IL-1ß.

View larger version (37K): [in this window] [in a new window]   Figure 2. A, Northern blot analysis of IGF-I mRNA response to increasing concentrations of IL-1ß in the presence or absence of rGH. Forty-eight-hour-old hepatocytes were incubated with increasing concentrations of IL-1ß (from 0.01–10 ng/ml) in presence or absence of rGH (500 ng/ml). Northern blot analysis was performed as indicated in Materials and Methods. IGF-I mRNA levels at the beginning of the experimental period (control 48 h) were used as control. B, Relative abundance of IGF-I mRNA in hepatocytes incubated with increasing concentrations of IL-1ß (from 0.01–10 ng/ml) in presence [GH (+)] or absence [GH (-)] of rGH (500 ng/ml). Each value represents the mean ± SEM of three separate experiments. *, P < 0.05; ***, P < 0.001 vs. the group GH (+) not exposed to IL-1ß.

View larger version (55K): [in this window] [in a new window]   Figure 3. A, Northern blot analysis of IGF-I mRNA (upper panel) and ß-actin mRNA (lower panel) after GH and cytokines treatment. Forty-eight-hour-old hepatocytes were incubated in presence or absence of rGH (500 ng/ml) and various cytokines (10 ng/ml). Northern blot analysis was performed as indicated in Materials and Methods. IGF-I mRNA levels at the beginning of the experimental period (control 48 h) were used as control. B, Relative abundance of IGF-I mRNA in hepatocytes incubated and various cytokines (10 ng/ml). Each value represents the mean ± SEM of three separate experiments. *, P < 0.05; **, P < 0.01; ***, P < 0.001 vs. the group GH (-) not exposed to cytokines.

Regulation of GHR/GHBP mRNAs
Dose-response curve to GH. To test whether the IL-1ß-induced inhibition of the IGF-I response to GH might be caused by alteration in the GHR gene expression, we investigated the regulation of GHR/GHBP mRNAs levels by IL-1ß. In our conditions, exposition of cells to various doses of GH for 24 h did not affect the GHR/GHBP expression. At each GH concentration tested, IL-1ß (10 ng/ml) decreased the GHR and GHBP mRNA levels (70% reduction on average, P < 0.001) (Fig. 4, A and B).

View larger version (46K): [in this window] [in a new window]   Figure 4. A Northern blot analysis of GHR/GHBP mRNAs response to increasing concentrations of GH in presence or absence of IL-1ß. Forty-eight-hour-old hepatocytes were incubated with increasing concentrations of rGH (from 1–500 ng/ml) in presence or absence of IL-1ß (10 ng/ml). Northern blot analysis was performed as indicated in Materials and Methods. GHR mRNA levels at the beginning of the experimental period (control 48 h) were used as control. B, Relative abundance of GHR mRNA in hepatocytes incubated with increasing concentrations of rGH (from 1–500 ng/ml) in presence [IL-1ß (+)] or absence [IL-1ß (-)] of IL-1ß (10 ng/ml). Each value represents the mean ± SEM of three separate experiments. ***, P < 0.001 vs. the group IL-1 (-), at any dose of GH.

View larger version (24K): [in this window] [in a new window]   Figure 5. A, Northern blot analysis of GHR/GHBP mRNAs response to increasing concentrations of IL-1ß in the presence or absence of rGH. Forty-eight-hour-old hepatocytes were incubated with increasing concentrations of IL-1ß (from 0.01–10 ng/ml) in presence or absence of rGH (500 ng/ml). Northern blot analysis was performed as indicated in Materials and Methods. GHR or GHBP mRNA levels at the beginning of the experimental period (control 48 h) were used as control. B, Relative abundance of GHR mRNA in hepatocytes incubated with increasing concentrations of IL-1ß (from 0.01–10 ng/ml) in presence [GH (+)] or absence [GH (-)] of rGH (500 ng/ml). Each value represents the mean ± SEM of three separate experiments. C, Relative abundance of GHBP mRNA in hepatocytes incubated with increasing concentrations of IL-1ß (from 0.01–10 ng/ml) in presence [GH (+)] or absence [GH (-)] of rGH (500 ng/ml). Each value represents the mean ± SEM of three separate experiments. *, P < 0.05; ***, P < 0.001 vs. the corresponding group [GH (+) or GH (-)] not exposed to IL-1ß.

View larger version (40K): [in this window] [in a new window]   Figure 6. A, Northern blot analysis of GHR/GHBP mRNAs after GH and cytokines treatment. Forty-eight-hour-old hepatocytes were incubated in presence or absence of rGH (500 ng/ml) and various cytokines (10 ng/ml). Northern blot analysis was performed as indicated in Materials and Methods. GHR or GHBP mRNA levels at the beginning of the experimental period (control 48 h) were used as control. B, Relative abundance of GHR mRNA in hepatocytes incubated in presence or absence of rGH (500 ng/ml) and various cytokines (10 ng/ml). Each value represents the mean ± SEM of three separate experiments. C, Relative abundance of GHBP mRNA in hepatocytes incubated in presence or absence of rGH (500 ng/ml) and various cytokines (10 ng/ml). Each value represents the mean ± SEM of three separate experiments. *, P < 0.05; **, P < 0.01 vs. the corresponding group [GH + or GH (-)] not exposed to cytokines.

LDH
The LDH release into the medium was not significantly affected by exposition of cells to GH and cytokines (w/o cytokines and GH: 1.8 ± 0.3%; w/o cytokines and w/GH: 1%; w/IL-1ß and w/o GH: 3.8 ± 0.8%; w/IL-1ß and GH: 2.5 ± 0.5%; w/TNF- and w/o GH: 3.3 ± 0.5%; w/TNF- and GH: 3%; not significant). All values were within the limits of the literature for a viable cell population.

	Discussion

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Our study shows, for the first time, that cytokines regulate the basal and the GH-stimulated IGF-I gene expression in hepatocytes. IL-1ß, and TNF- to a lesser extent, inhibits the GH-stimulated IGF-I gene expression without affecting its basal expression. In contrast, IL-6 stimulates the basal IGF-I gene expression without affecting its GH-stimulated expression.

Although a direct effect of cytokines on basal IGF-I gene expression already has been reported in other cell types [Leydig cells (21, 22), osteoblasts (23), chondrocytes (24), and macrophages (25)], their effect on the GH-induced IGF-I mRNA response had not been investigated. Our present finding of an inhibition of the IGF-I mRNA response to GH by IL-1ß suggests that this cytokine impairs the stimulatory action of GH on the hepatocyte IGF-I gene. Our data therefore extend the in vivo observations made by Fan et al. (7). These authors indeed brought evidence supporting the role of IL-1ß and TNF- in the decline of IGF-I after endotoxin injection (8, 26). In contrast to their findings, which suggest that the inhibition of IGF-I by IL-1ß is mediated by glucocorticoids, our data support a direct role for IL-1ß in the decline of circulating IGF-I. Further experiments will determine whether the changes in IGF-I mRNA, induced by IL-1ß, result from alterations in gene transcription or mRNA stability. Indirect evidence suggests that sepsis and endotoxin injection induce a state of GH resistance in vivo (26, 27). Our study clearly establishes IL-1ß as a cause of resistance of the IGF-I gene to the GH stimulation. The mechanisms whereby IL-1ß induces a state of GH resistance in hepatocytes, however, are unknown. Our data show that the IL-1ß-induced GH resistance is associated with decreased GHR gene expression. The parallel decrease of GHR mRNA and GH-stimulated IGF-I mRNA in response to IL-1ß suggests a causal relationship between the two phenomenons. This observation suggests, therefore, that the GH resistance induced by IL-1ß might be caused by a reduction of the hepatocyte GHR number, which might be reflected by the major decrease in GHR mRNA. Such a mechanism has been described for PDGF, whose receptors on osteoblasts are decreased by proinflammatory cytokines such as IL-1ß and TNF- (28). The parallel decline of IGF-I and GHR mRNAs, in response to increasing concentrations of IL-1ß, does not represent a toxic effect on the hepatocyte. Indeed, the absence of significant changes in the LDH release and the positive response of ß-actin in cells exposed to IL-1ß indicate that our observations do not reflect a toxic phenomenon. Cytokines, especially TNF-, have been reported to impair the phosphorylation by insulin of its receptor (29), thus causing insulin resistance (30). Because the first step of the GH transduction pathway involves a phosphorylation of its receptor, its inhibition by cytokines might also contribute to the induction of a state of GH resistance. An increasing number of cytokine effects seems to be mediated through nitric oxide (NO) production (31, 32). Cytokines, especially IL-1ß and TNF-, have been shown to stimulate inducible NO synthase in hepatocytes (33, 34). Increased NO production by hepatocytes, therefore, might be one of the mechanisms involved in the inhibitory action of IL-1ß on the GH-stimulated IGF-I expression. Finally, the effect of IL-1ß on the hepatocyte might involve other pathways such as activation of NFkB (35) or sphingomyelin hydrolysis (36).

Our study did not investigate whether other GH actions also may be inhibited by IL-1ß. However, previous experiments of others suggest that exposition of hepatocytes to IL-1ß may inhibit the stimulation of cytochrome P450 2C12 (CYP2C12) by GH (37). The suppressive effect of IL-1ß on the GH-stimulated expression of both IGF-I and CYP2C12 gene expression favors the hypothesis that IL-1ß impairs a transduction pathway that is necessary for the transcriptional activation by GH of these two genes.

In contrast to IL-1ß and TNF-, IL-6 stimulates the IGF-I gene expression in hepatocytes and therefore mimicks the GH action on IGF-I gene. This observation may suggest a common mechanism of action for GH and IL-6 on the IGF-I gene. Indeed, in addition to interacting with a receptor belonging to the same superfamily (38, 39), GH and IL-6 share at least one common transduction pathway factor, namely STAT-3, or acute phase-reactant factor (40). The role of STAT-3 in the GH-stimulated transcription of IGF-I gene, however, is not established. The IL-6-induced stimulation of IGF-I is not additive to that induced by GH. This may signify that in our experiments the IGF-I stimulation is already maximal. This interpretation is indeed supported by the dose-response curve of the IGF-I mRNA in response to GH, showing a maximal stimulation of the IGF-I gene expression by 500 ng/ml of GH.

Because IL-1ß and IL-6 exert in vitro opposite actions on IGF-I gene expression, and IL-1ß is generally produced together with IL-6, we tested whether IL-1ß and IL-6 may interact in the regulation of IGF-I gene expression. Our data show that the stimulatory action of IL-6 is completely blunted by IL-1ß, whether in the presence or in the absence of GH. Nevertheless, the inhibition by IL-1ß of this action of IL-6 is not a generalized phenomenon because IL-1ß and IL-6 can act additively or synergistically on several positive acute-phase reactant (41) and cytochrome genes [i.e. CYP2C11 (42)].

The physiological relevance of our findings is supported by the dose-response curve of the IL-1ß effect on the GH-stimulated IGF-I and GHR expression. The half-maximal effect of IL-1ß is observed around 0.1–1 ng/ml, a concentration close to peripheral circulating concentations of IL-1ß observed in sepsis (between 0.01 and 1 ng/ml). This IL-1ß half-maximal dose is similar to that reported for other actions of IL-1ß, especially its inhibition of expression of cytochromes P450 1A1 and 2C11 in hepatocytes (42, 43). Furthermore, the paracrine interaction between hepatocytes and cytokines producing cells (Kupffer), make local concentrations ever higher than those reached in the peripheral circulation.

Recent observations showed that endotoxin injection in rats decreases circulating IGF-I concentrations (6) (personal observation). Our present results suggest that decreased circulating IGF-I in response to endotoxin may be caused, at least partially, by a direct effect of some cytokines at the hepatocyte level. Indeed, the minor contribution of nonparenchymatous cells in our culture strongly indicates that the changes observed in IGF-I expression occur in hepatocytes. The demonstration of high-affinity IL-1 receptors on primary cultured hepatocytes (44) reinforces this hypothesis. Furthermore, the attenuation by IL-1ß receptor antagonist of the sepsis-induced decrease in plasma IGF-I also suggests a role for endogenous IL-1ß production in the infection-induced decline of IGF-I (26). Indirect mechanisms, such as decreased GH secretion (11), anorexia (45), and increased glucocorticoids production (6), may also contribute to the decline of IGF-I caused by endotoxin injection.

Our report that IL-1ß induces GH resistance also may have significance with regard to the observations of failure of GH to increase plasma IGF-I (46) and to alter the catabolic response (27) in critically ill patients. Plasma, or more often, local cytokines concentrations, which are increased in a large number of catabolic situations (47, 48), may indeed impede the anabolic action of GH.

Our findings establish the possibility of a physiological role for the major inflammatory cytokines in the regulation of hepatocyte IGF-I and GHR gene expression.

	Acknowledgments

 
We thank Jean-Marie Ketelslegers for continuous support, helpful discussions, and his review of the manuscript.

	Footnotes

 
¹ This work was supported by grants from the Belgian National Fund for Scientific Research (3.4559.93), from the Fund for Scientific Development (to J.P.T.), University of Louvain (Belgium), and from the DANONE Institute (Brussels, Belgium). Presented in part at the 10th International Congress of Endocrinology, San Francisco, CA, 1996.

² A Research Associate from the National Fund for Scientific Research (Belgium).

Received August 19, 1996.

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