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Unité de Diabétologie et Nutrition, Université Catholique de Louvain, B-1200 Brussels, Belgium; U-376, INSERM, Hopital Arnaud de Villneuve (A.L.C.), 34295 Montpellier, France; and U-344, INSERM, Hôpital Necker (M.E.), 75730 Paris, France
Address all correspondence and requests for reprints to: Jean-Paul Thissen, M.D., Diabetes and Nutrition Unit, avenue Hippocrate 54, 1200 Brussels, Belgium. E-mail: thissen{at}diab.ucl.ac.be
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF) induce a state of GH
resistance. A new family of suppressors of cytokine signaling (SOCS),
induced by cytokines activating the Janus kinase (JAK)-signal
transducer and activator of transcription (STAT) pathway, has been
recently identified as a negative feedback loop of intracellular
signaling. Overexpression of some SOCS (SOCS-3, CIS, and SOCS-2) has
been reported to inhibit the JAK-STAT pathway stimulated by GH. To
assess the possible role of these three SOCS proteins in the GH
resistance induced by endotoxin and cytokines, we investigated the
regulation of their gene expression by endotoxin and GH in rat liver
and by proinflammatory cytokines and GH in primary culture hepatocytes.
Both GH and lipopolysaccharide induced the three SOCS messenger RNAs
(mRNAs) in vivo. In vitro, GH also
increased the liver mRNAs encoding SOCS-2, SOCS-3, and CIS. Although
IL-1ß and TNF alone induced only weakly the expression of SOCS-3
and CIS, these cytokines strongly potentiated the induction of these
two SOCS by GH. In contrast, IL-6 alone markedly induced SOCS-3 mRNA,
but did not potentiate the GH action on SOCS-3 and CIS mRNAs. The GH
induction of SOCS-2 was not potentiated by any of these cytokines.
Considering the ability of these SOCS to inhibit the JAK-STAT pathway
induced by GH, these results suggest that the overexpression of SOCS-3
and CIS mRNAs induced by IL-1ß and TNF or by endotoxin in
vivo may play a role in the GH resistance induced by sepsis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF) play a major role in
the decrease in circulating IGF-I in response to sepsis (10, 11). Furthermore, recent experimental observations from our
laboratory (12, 13) and others (14, 15) have
shown that the decrease in liver IGF-I production associated with
sepsis results from a state of GH resistance. Such a state of GH
resistance has also been described in patients with sepsis, thus making
the rat animal model very relevant (4). However, the
mechanisms responsible for the GH resistance induced by cytokines are
still unclear. Recently, a new family of inhibitors of cytokine receptor-induced signaling has been identified and named suppressors of cytokine signaling or SOCS (SOCS-1 to -7 and CIS) (16). These proteins are induced by cytokines activating the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and may act as a negative feedback loop. The inhibitory action of SOCS on this transduction pathway results from their binding to either activated JAKs or the receptor to inhibit the docking of STAT to the tyrosine-phosphorylated domain of the receptor (17, 18, 19). GH itself induces the expression of at least three SOCS (SOCS-3, CIS, and SOCS-2) in several tissues, including the liver (20, 21). Furthermore, overexpression of these SOCS in cells has been reported to inhibit the JAK-STAT pathway initiated by GH, suggesting their role in the cellular regulation of GH action (19, 21, 22, 23).
Considering the ability of these SOCS to block GH action, we hypothesized that GH resistance induced by lipopolysaccharide (LPS) in vivo and by proinflammatory cytokines in vitro might be caused by the overexpression of SOCS in liver.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Exp 1: effect of GH on liver SOCS gene expression. Eight-week-old male Wistar rats hypophysectomized at 5 weeks and weighing 102 ± 4 g (mean ± SD) were obtained from IFFA-CREDO (Lyon, France). They were housed under controlled conditions of lighting (12 h of light, from 0700–1900 h). After a 7-day adaptation period to unlimited food and water access, rats received one sc injection of rat GH (100 µg/100 g BW) on the morning of the eighth day and were killed at different times after injection (0, 1, 3, 6, 9, and 12 h). Blood was collected into glass tubes, centrifuged (1800 rpm, 10 min, 4 C), and serum was stored at -20 C until analysis. Livers were removed, weighed, frozen in liquid nitrogen, and stored at -80 C until analysis (three rats per group).
Exp 2: effect of LPS on liver SOCS gene expression. The second experiment used 8-week-old male Wistar rats, weighing 246 ± 12 g (mean ± SD), obtained from Katholieke Universiteit (Leuven, Belgium). They were housed under controlled conditions of lighting (12 h of light, from 0700–1900 h). Food was only available between 1800–0900 h, whereas access to water was unlimited. After a 7-day adaptation period, rats received on the morning of the eighth day one ip injection of LPS (750 µg/100 g BW) and were killed at different times after injection (0, 1, 2, 3, 6, and 12 h). Blood was collected, and serum was stored at -20 C until analysis. Livers were removed and stored at -80 C until analysis (three rats per group).
In vitro experiments
Reagents. rGH (AFP-87401; B-13) was a gift from the NIDDK.
Recombinant rat IL-1ß and TNF were purchased from R and D Systems (Abingdon, UK). Recombinant murine IL-6 was a gift from
J. Van Snick and J. C. Renauld (ICP, Brussels, Belgium).
Collagenase (type B) was purchased from Roche Molecular Biochemicals (Mannheim, Germany). Plastic dishes manufactured by
Nunc (Roskilde, Denmark) and DMEM/Ham’s F-12 medium were purchased
from Life Technologies, Inc. (Paisley, Scotland).
Animals. For the in vitro experiments, 6-week-old male Wistar rats (Katholieke Universiteit, Leuven, Belgium), weighing 188 ± 44 g (mean ± SD), were maintained under controlled conditions of lighting (12 h of light, from 0700–1900 h) and temperature with free access to food and water.
Hepatocyte isolation and primary cell culture. Rat
hepatocytes were obtained using a protocol detailed previously
(24). Briefly, Matrigel was prepared from
Engelbreth-Holm-Swarm sarcoma propagated in C57BL/6 female mice, stored
at -20 C, and spread on 60-mm plastic dishes. Hepatocytes were
prepared by nonrecirculating collagenase perfusion through the portal
vein of rats anesthetized with pentobarbital (60 mg/kg). Cells were
cultured in DMEM/Ham’s medium supplemented with
penicillin/streptomycin (100 U/ml and 100 µg/ml, respectively), with
hydrocortisone (5 x 10-8 M)
and insulin (1.75 x 10-7 M) as
the sole hormones. Cells were maintained at 37 C in a humidified
incubator containing 5% CO2. After 48 h of
culture, cells were incubated for different times (30, 60, or 180 min)
in serum-free DMEM/Ham’s F-12 medium supplemented as previously
described and containing rGH (500 ng/ml), IL-1ß (10 ng/ml), IL-6 (10
ng/ml), and TNF (10 ng/ml), alone or in combination. Each experiment
was performed four times, and in each experiment, each value represents
a pool of four 60-mm plates.
Northern blot analysis. Total RNA was prepared by the guanidine isothiocyanate-cesium chloride method (25). RNA (20 µg) was denatured in formaldehyde-3-[N-moyholino]propanesulfonic acid, subjected to gel electrophoresis in 1% agarose, and transferred to nylon membranes (Hybond, Amersham Pharmacia Biotech, Aylesbury, UK) by capillary transfer overnight. Levels of SOCS-2, SOCS-3, and CIS messenger RNAs (mRNAs) were determined by hybridization with specific murine complementary DNA probes labeled by random priming (Amersham Pharmacia Biotech). These complementary DNAs, containing the entire open reading frame and provided by D. Hilton’s laboratory (17), were amplified in pEF-Flag I plasmid, and inserts were released by XbaI. To verify uniform loading, control hybridization was performed with a 23-mer 18S oligonucleotide synthesized on a DNA synthesizer and end labeled with [32P]ATP by T4 polynucleotide kinase (Amersham Pharmacia Biotech). The mRNA levels were quantified by densitometric scanning of the hybridization signal (Ultroscan XL laser densitometry, LKB, Bromma, Sweden) with the use of software (Gel Scan, Pharmacia Biotech, Uppsala, Sweden). The results are expressed as a percentage of the control value, usually the value measured at the time zero. Because CIS and SOCS-2 expression was undetectable in vitro at time zero, the maximal value measured in these experiments (GH 60 min and GH 180 min, respectively) was assigned as the control value.
Immunoprecipitation and Western blotting. The lysates (26, 27) of livers were incubated with anti-SOCS-3 antibody (2 µl, 200 µg/ml; SC 7020, Santa Cruz Biotechnology, Inc., Santa Cruz, CA) and collected using protein A-agarose. Immunoprecipitated proteins were separated by SDS-PAGE (15%; 0.5 mg protein/well), transferred onto a polyvinylidene difluoride transfer membrane (Polyscreen, NEN Life Science Products, Boston, MA), immunodetected with an appropriate antibody to SOCS-3 (SC 7020, Santa Cruz Biotechnology, Inc.; 1:1000), and visualized by enhanced chemiluminescence (Amersham Pharmacia Biotech). The experiment was repeated three times with a liver lysate from a different animal at each time point.
Statistical analysis
Experimental data are presented as the mean ±
SEM. Data were analyzed by ANOVA, followed by Newman-Keuls
test for in vitro experiments and Tukey-Kramer test for
in vivo experiments. In addition, for in vitro
data, the area under the curve calculated by the trapezoidal method was
analyzed by ANOVA, followed by Newman-Keuls test. Statistical
significance was set at P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 2).
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, A and D). SOCS-3 mRNA levels peaked
1 h after GH injection (17-fold increase vs. time zero,
P < 0.001) and rapidly decreased to return to basal
levels as early as 9 h. CIS mRNA was also markedly induced by GH
(13-fold increase at 1 h; P < 0.001; Fig. 1, B
and D). Similarly to SOCS-3 and CIS, SOCS-2 mRNA peaked 1 h after
GH injection, but with a smaller amplitude (7-fold increase
vs. time zero, P < 0.01) and returned to
the basal level at 6 h (0.7-fold increase, P = NS;
Fig. 1, C and D).
LPS administration in intact rats also induced the expression of these
three SOCS mRNAs. The increase in SOCS-3 mRNA was slightly apparent at
1 h, peaked at 2 h (9-fold increase vs. time zero,
P < 0.01) before declining slowly to return to basal
level at 12 h (6 h: 4-fold increase, P < 0.01;
12 h: 2-fold increase, P = NS; Fig. 2, A and E). SOCS-3 protein was also
strongly induced by LPS, with a peak at 3 h and a rapid decline to
return to the basal level at 6 h (Fig. 2D). Induction of CIS mRNA
was also detected 1 h after LPS injection (Fig. 2, B and E), with
a peak at 2 h (2.7-fold increase at 2 h; P <
0.01) and a slow decline toward low levels at 12 h. The
stimulation of SOCS-3 and CIS mRNAs by LPS was slower but more
prolonged than that after GH in hypophysectomized animals. SOCS-2 mRNA
was also stimulated by LPS treatment, peaking at 1 h (3.5-fold
increase; P = NS) and rapidly declining to return to
the basal level at 6 h (3 h: 1.2-fold increase, P
= NS; Fig. 2, C and E).
In vitro experiments
Because LPS induces in vivo the release of
proinflammatory cytokines such as IL-1ß and TNF, which are able to
induce a state of GH resistance (13), we decided to
investigate the ability of these cytokines to directly stimulate SOCS
gene expression in cultured hepatocytes. In the absence of any
stimulation, the expression of SOCS-2 and CIS was almost undetectable
in primary cultured hepatocytes.
Effect of GH
In agreement with our in vivo data, GH stimulated the
expression of the three SOCS in primary cultured hepatocytes. GH
rapidly and transiently increased SOCS-3 mRNA, with a peak at 30 min
(5-fold increase vs. control at 30 min, P <
0.01; Fig. 3). The time course of the CIS
mRNA response to GH showed an early and important peak at 60 min
(14-fold increase vs. control at 60 min, P
< 0.001), followed by a slow decrease (Fig. 4). The induction of SOCS-2 gene
expression was weaker and delayed, and increased continuously until 180
min, the last point examined (8-fold increase vs. control at
180 min, P < 0.001; Fig. 5).
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, A and B) only
weakly induced the expression of SOCS-3 mRNA (4-fold increase
vs. control at 60 min, P < 0.001), the
combination of IL-1ß and GH strongly induced SOCS-3 gene expression,
with a peak at 60 min (25-fold increase vs. control at 60
min, P < 0.001). IL-1ß potentiated the effect of GH
on SOCS-3 gene expression (5-fold at 60 min; IL-1ß/GH vs.
GH, P < 0.001). The effect of TNF was qualitatively
similar to that of IL-1ß, but less marked (Fig. 3, C and D). TNF
alone did not induce SOCS-3 mRNA, but in combination with GH, it
markedly induced SOCS-3 mRNA (27-fold increase vs. control
at 60 min, P < 0.001). Like IL-1ß, TNF also
potentiated the effect of GH on SOCS-3 mRNA (2.7-fold at 60 min,
TNF-/GH vs. GH, P < 0.05). In contrast
to IL-1ß and TNF, IL-6 alone increased dramatically the expression
of SOCS-3 in hepatocytes, with a peak at 30 min (37-fold increase;
P < 0.001; Fig. 3, E and F). However, the combination
of IL-6 and GH did not amplify the effect of GH on SOCS-3 gene
expression (IL-6/GH vs. GH, P = NS).
CIS mRNA. CIS mRNA was induced by IL-1ß (6-fold increase
vs. control at 180 min, P < 0.01).
Furthermore, when combined with GH, IL-1ß amplified the GH-induced
CIS mRNA as early as 60 min (3-fold at 60 min; IL-1ß/GH
vs. GH, P < 0.05). Similarly, TNF weakly
induced CIS mRNA (6-fold increase vs. control at 60 min,
P < 0.01). Like IL-1ß, TNF potentiated the effect
of GH on the induction of CIS mRNA (2-fold at 60 min; TNF/GH
vs. GH, P < 0.001). In contrast with its
strong inductive effect on SOCS-3 mRNA, IL-6 did not induce CIS mRNA
(only 2.5-fold increase vs. control at 60 min,
P = NS). Even combined with GH, IL-6 did not increase
CIS gene expression (GH/IL-6 vs. GH, P =
NS).
SOCS-2 mRNA. Like the other SOCS, SOCS-2 mRNA was induced by
IL-1ß. The stimulation was detectable at 60 min and slowly increased
until 180 min, the last point examined (3-fold increase vs.
control at 180 min, P < 0.05; Fig. 5, A and B). The
effects of IL-1ß and GH on SOCS-2 expression were only additive and
not synergistic, in contrast with other SOCS (1.3-fold at 180 min;
IL-1ß/GH vs. GH, P = NS). TNF (Fig. 5, C and D) and IL-6 (Fig. 5, E and F) alone did not induce SOCS-2 gene
expression, and when combined with GH, they did not potentiate the
effect of GH on this gene (TNF/GH vs. GH,
P = NS; IL-6/GH vs. GH, P =
NS).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SOCS proteins have been identified by their ability to inhibit the intracellular signal initiated by cytokines (16, 28, 29). Because SOCS are cytokine-inducible proteins that inhibit the JAK-STAT pathway, it has been suggested that they may act in a classical negative feedback loop that contributes to termination of the intracellular signal (18, 30). This feedback system is probably also operational to control the action of GH, one member of the cytokine superfamily. We show, as previously reported by others (20, 21), that GH induces liver SOCS-3, CIS, and SOCS-2 mRNA concentrations in both cultured hepatocytes and hypophysectomized rats. The amplitude and kinetics of SOCS mRNAs induction by GH in these rats are similar to those observed in intact animals (21). The stimulation of SOCS-3 mRNA by GH was weaker in vitro than in vivo. This discrepancy may result from the down-regulation of STAT-5, the transcriptional factor responsible for the GH induction of SOCS-3, by continuous exposition to GH, as is the case in vitro (31). Furthermore, overexpression of SOCS has been reported by different researchers to inhibit the induction by GH of the JAK-STAT pathway, in particular STAT-5 activation (19, 21, 22, 23). Taken together, these observations suggest that these three SOCS proteins probably participate in the termination of the GH signal.
The main finding of our studies is that the GH resistance induced by
LPS in vivo and by IL-1ß and TNF in vitro is
associated with overexpression of these three SOCS in the liver.
Because LPS acts in vivo mainly by stimulating the release
of several cytokines, such as IL-1ß, TNF, and IL-6, our data
suggest that the induction of SOCS by LPS is probably the consequence
of the direct action of these cytokines on the hepatocyte. GH, despite
its stimulatory effect on SOCS expression, does not seem to play a role
in the induction of SOCS by LPS, because its secretion is reduced in
the rat exposed to LPS (12, 32), in contrast to that in
humans (4, 5).
Our data show that LPS and proinflammatory cytokines regulate
differently the three SOCS genes in hepatocytes. Among the three
cytokines tested, IL-1ß and TNF exert similar actions on SOCS-3
and CIS genes. Indeed, IL-1ß and, to a lesser extent, TNF strongly
potentiate the induction of these SOCS by GH. However, IL-1ß and
TNF alone very weakly induce SOCS-3 and CIS expression in
hepatocytes, in contrast to that in hemopoietic and immune cells
(17, 33). The relative failure of IL-1ß and TNF alone
to stimulate SOCS-3 and CIS mRNAs in hepatocytes is compatible with the
observation that the JAK-STAT pathway used to activate transcription of
the SOCS genes is not stimulated by these two cytokines
(34). The mechanisms by which IL-1ß and TNF
potentiate the effects of GH on these SOCS genes therefore remains
unknown. One possibility would be that these two cytokines stimulate
SOCS gene expression by inducing specific isoforms of STAT (LIL-STAT,
STAT3 isoform), which are, in turn, susceptible to potentiate the
transcriptional activity of classical STATs (such as STAT-3 and -5)
induced by GH (35, 36).
Previous studies have shown that overexpression of SOCS-3 and CIS can
clearly inhibit the activation of STAT-5 by GH. In particular, the role
of CIS as an inhibitor of STAT-5 activation has been recently
reinforced by the demonstration that transgenic mice overexpressing CIS
present a phenotype similar to that of STAT5 knockout mice
(37). Inhibition of STAT-5 docking to the
tyrosine-phosphorylated domain of the GH receptor appears to be the
principal mechanism responsible for CIS-induced inhibition of GH
transduction pathway (37). SOCS-3, in contrast, has been
suggested to act by binding to the JAK2 tyrosine kinase domain to exert
directly its inhibitory effect on GH signaling. It is still not clear
how this binding inhibits the tyrosine kinase activity of JAK-2
(19). Evidence indicates that the inhibition of STAT-5 in
response to GH can contribute to a state of GH resistance. Indeed,
based on the observations made in knockout mice or in cell transfection
systems, STAT-5 plays a major role in the mediation of transcriptional
activation by GH of several genes, such as IGF-I (38, 39),
Spi2.1 (40), and the acid-labile subunit of the
150-kDa IGFBP complex (41). As we previously showed
(12, 13, 42, 43), the stimulatory action of GH on these
three genes is blunted by LPS in vivo and by IL-1ß and
TNF in vitro. Taken together, these observations support
the conclusion that LPS in vivo and IL-1ß and TNF
in vitro might induce GH resistance by amplifying the
negative feedback loop caused by overexpression of SOCS-3 and CIS
(44).
Although it is also a proinflammatory cytokine, IL-6 induces a
different profile of SOCS expression in hepatocytes. In contrast to
IL-1ß and TNF, IL-6 alone stimulates SOCS-3 mRNA and does not
potentiate the effect of GH on this gene. The ability of IL-6 to
stimulate SOCS-3 has been reported in other cellular systems
(17). This property of IL-6 is shared by other members of
this family of cytokine, as leptin and ciliary neurotropic factor have
been reported to induce SOCS-3 gene expression in the hypothalamus
(30, 45). Furthermore, IL-6 does not stimulate CIS mRNA in
hepatocytes. This may result from the fact that CIS induction relies on
STAT-5 activation (46, 47), whereas IL-6 seems to
stimulate mostly STAT-3 (48, 49).
Despite inducing SOCS-3 expression, IL-6 does not induce a state of GH resistance in primary cultured hepatocytes, as previously reported by us (13, 42) and confirmed by others (50). This suggests that the induction of SOCS-3 by IL-6 cannot by itself block the GH action on IGF-I and Spi2.1 genes. Because the intracellular action of IL-6 is mediated essentially through the phosphorylation of STAT-3 by JAK-1 and not JAK-2 (51), it is possible that the IL-6-induced SOCS-3 does not inhibit the JAK-2-mediated GH signaling. However, SOCS gene transfection experiments have not yet addressed the question of the specificity of the SOCS action.
The consequences of SOCS-2 induction by GH and cytokines are less clear. SOCS-2 has been shown to act either as an enhancer (21) or as a down-regulator (22) of STAT-5 activation by GH. The regulation of SOCS-2 by GH and IL-1ß may agree with the hypothesis that SOCS-2 play a role as a down-regulator of the JAK-STAT pathway like the other SOCS. Alternatively, SOCS-2 might physiologically act to remove the negative feedback loop on JAK-STAT-dependent GH signaling to resensitize it for potential further activation (22). The late and progressive induction of SOCS-2 mRNA supports this hypothesis. Moreover, more studies aiming at defining the role and the function of SOCS-2 will be necessary to understand its implication in GH signaling.
In summary, the present study reports, for the first time, the
potentiation by IL-1ß and TNF of GH-induced SOCS-3 and CIS, known
as feedback inhibitors of the JAK-STAT pathway. Considering that these
two proinflammatory cytokines and LPS induce GH resistance, these
results suggest that overexpression of SOCS-3 and CIS may play a role
in the GH resistance induced by sepsis, as well as other mechanisms,
such as reduction of GH receptors (12).
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Acknowledgments |
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Footnotes |
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Received March 21, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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of the insulin-like
growth factor I messenger ribonucleic acid response to growth hormone
in rat hepatocyte primary culture. Endocrinology 138:1078–1084
induce SOCS3 mRNA and inhibit IL-6-induced activation of STAT3 in
macrophages. FEBS Lett 463:365–370[CrossRef][Medline]
-interferon-activated sequence mediates the growth hormone induction
of the mouse acid-labile subunit promoter in liver cells. Mol
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G. Yumet, M. L. Shumate, P. Bryant, C.-M. Lin, C. H. Lang, and R. N. Cooney Tumor necrosis factor mediates hepatic growth hormone resistance during sepsis Am J Physiol Endocrinol Metab, September 1, 2002; 283(3): E472 - E481. [Abstract] [Full Text] [PDF]
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V. Beauloye, B. Willems, V. de Coninck, S. J. Frank, M. Edery, and J.-P. Thissen Impairment of Liver GH Receptor Signaling by Fasting Endocrinology, March 1, 2002; 143(3): 792 - 800. [Abstract] [Full Text] [PDF]
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C. Ling and H. Billig PRL Receptor-Mediated Effects in Female Mouse Adipocytes: PRL Induces Suppressors of Cytokine Signaling Expression and Suppresses Insulin-Induced Leptin Production in Adipocytes in Vitro Endocrinology, November 1, 2001; 142(11): 4880 - 4890. [Abstract] [Full Text] [PDF]
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R. A. Mooney, J. Senn, S. Cameron, N. Inamdar, L. M. Boivin, Y. Shang, and R. W. Furlanetto Suppressors of Cytokine Signaling-1 and -6 Associate with and Inhibit the Insulin Receptor. A POTENTIAL MECHANISM FOR CYTOKINE-MEDIATED INSULIN RESISTANCE J. Biol. Chem., July 6, 2001; 276(28): 25889 - 25893. [Abstract] [Full Text] [PDF]
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