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Departamento de Fisiología, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain
(Requests for offprints should be addressed to A López-Calderón; Email: ALC{at}med.ucm.es)
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Abstract |
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(TNF-) and nitrites (P < 0.01). Pretreatment of the animals with gadolinium chloride blocked the inhibitory effect of LPS on body weight, and on serum concentrations of IGF-I, IGFBP-3 and nitrites, as well as growth hormone receptor (GHR), IGF-I and IGFBP-3 gene expression in the liver. In contrast, gadolinium chloride administration did not modify the stimulatory effect of LPS on serum concentrations of ACTH, corticosterone and TNF-. These results suggest that Kupffer cells are important mediators in the inhibitory effect of LPS on GHR, IGF-I and IGFBP-3 gene expression in the liver, leading to a decrease in serum concentrations of IGF-I and IGFBP-3. |
Introduction |
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Endotoxin, also known as lipopolysaccharide (LPS), is a component of the wall of Gram-negative bacteria, which triggers the physiological and endocrinological responses to sepsis. Endotoxin administration in rats increases plasma concentrations of corticosterone, whereas it decreases circulating IGF-I and its gene expression in the liver (Soto et al. 1998, Defalque et al. 1999). The adult liver is the main source of circulating IGF-I and its main serum-binding protein, IGF-binding protein-3 (IGFBP-3), which are synthesized by different cell populations. IGF-I is synthesized mainly by hepatocytes, whereas IGFBP-3 is released by nonparenchymal cells such as Kupffer, endothelial and hepatic stellate cells. The inhibitory effect of LPS on the IGF-I axis is also exerted at the IGFBP-3 level, since there is a decrease in serum concentration of this protein and its synthesis in the liver in LPS-treated rats (Priego et al. 2003a). Similarly, humans with chronic inflammatory illnesses have decreased serum concentrations of IGF-I and IGFBP-3 (Katsanos et al. 2001).
LPS-induced decrease in serum concentrations of IGF-I and IGFBP-3 is due to a direct inhibitory effect of LPS on liver IGF-I and IGFBP-3 gene expression, regardless of pituitary GH secretion (Defalque et al. 1999, Priego et al. 2003b). Induction of inducible nitric oxide synthase (iNOS) during sepsis is involved in the inhibition of IGF-I–IGFBP-3 after LPS administration (Priego et al. 2004).
LPS induces liver injury and the death of hepatocytes, which may have a role in liver dysfunction in sepsis (Nolan 1981). The liver plays a central role in the LPS response because it clears LPS from circulation and responds to LPS by releasing cytokines and reactive oxygen intermediates. Most of the toxicities of LPS in the liver have been related to those inflammatory mediators (for review see Su 2002). Kupffer cells represent the main cellular mediators of the effects of LPS in the liver. They play an important role in clearing LPS from blood (Mathison & Ulevitch 1979), and in releasing cytokines as well as other inflammatory molecules of the acute phase response. During inflammation, hepatocytes respond to products secreted by Kupffer cells with several metabolic changes, such as a decreased glucose production as a result of inhibition of enzymes involved in gluconeogenesis (Yerkovich et al. 2004). Inactivation of Kupffer cells prevents LPS-induced hepatocyte apoptosis and inhibits liver injury (Hamada et al. 1999). For that reason, it has been postulated that Kupffer cells or hepatic macrophages mediate most of deleterious effect in liver injury.
Gadolinium chloride is a Kupffer cell inhibitor. Use of gadolinium chloride is a suitable approach to studying the in vivo function of large Kupffer cells, since circulating monocytes and other macrophages are less vulnerable to gadolinium than Kupffer cells (Hardonk et al. 1992). Intravenously injected gadolinium chloride blocks Kupffer cell phagocytosis and the subsequent release of its mediators such as cytokines and nitric oxide after LPS administration (Hardonk et al. 1992). Furthermore, gadolinium administration reduces mortality (Roland et al. 1999) and liver injury (Lee et al. 2004) in sepsis.
The aim of this work was to analyse the role of Kupffer cells in LPS-induced inhibition of liver IGF-I and IGFBP-3 and activation of ACTH (corticotropin) and corticosterone secretion. The serum concentrations of tumour necrosis factor- (TNF-) and nitrites/nitrates were also analysed, as they are increased during the inflammatory response and may affect the endocrine system. The results suggest that Kupffer cells activated by LPS are involved in LPS-induced inhibition of liver IGF-I and IGFBP-3 gene expression and consequently in the decreased circulating levels of these proteins.
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Material and Methods |
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Male Wistar rats weighing 250–300 g (Harlam, Barcelona, Spain) were housed three or four per cage, under controlled conditions of temperature (22 °C) and light (lights on from 07:30 to 19:30 h). Food and water were available ad libitum. The procedures followed the guidelines recommended by the European Union for the care and use of laboratory animals.
Rats were randomly assigned to treatment group after 1-week adaptation to environment and diet. The day before start the LPS treatment, 20 rats were i.v. injected with 10 mg/kg gadolinium chloride (Sigma Chemical Co.) and 20 rats were i.p. injected with sterile saline, under halothane anaesthesia. This gadolinium protocol was shown to inhibit phagocytosis by rat liver Kupffer cells, and to reduce their response to LPS stimulation (Hardonk et al. 1992). The following day each group was divided in two groups; the first group received an i.p. injection of 1 mg/kg LPS (serotype 055:B5; Sigma Chemical Co.), and the second group received 250 µl sterile saline i.p. Rats received the LPS treatments at 17:30 h and at 08:30 h the following day. All animals were killed by decapitation at 12:30 h, 19:00 h after the first and 4 h after the second LPS, in a separate room, within 30 s of being removed from their cages. Blood was allowed to clot, and the serum was stored at –20 °C for IGF-I, IGFBP-3, corticosterone and nitrite assays, and at –80 °C for ACTH and TNF- assays. Immediately after decapitation the liver was removed, dissected, frozen in liquid nitrogen and stored at –80 °C until RNA extraction was performed.
Hormone and TNF- determination
Serum IGF-I concentrations were measured by a double-antibody RIA. The IGF-I antiserum (UB2–495) was a gift from Dr Underwood and Dr Van Wik (University of Maryland School of Medicine, Baltimore, MD, USA), and it is distributed by the Hormone Distribution Program of NIDDK through the National Hormone and Pituitary Program. Levels of IGF-I were expressed in terms of IGF-I from Gropep (Adelaide, Australia). The intra-assay coefficient of variation was 8%. All samples were run in the same assay.
Serum concentrations of corticosterone were determined by a competitive protein-binding assay. ACTH and TNF- serum levels were measured by RIA and ELISA with commercial kits from Diagnostic System Laboratories (Webster, TX, USA) and Amersham Biosciences.
Nitrite determination
Nitrite and nitrate concentrations in serum were measured by a modified version of the Griess assay, described by Miranda et al.(2001). Serum was deproteinized to reduce turbidity by centrifugation through a 30 kDa filter using a Centrifree Micropartition Device with a YM-30 ultra-filtration membrane (Amicon Division, Millipore Corporation, Bedford, TX, USA), at 15 000 r.p.m. for 1 h at 37 °C for 300 µl samples. Filtrated serum (100 µl) or 1/10-diluted culture medium was mixed with 100 µl vanadium chloride, followed quickly by the addition of the Griess reagents. The determination was performed after incubation at 37 °C for 30 min. The absorbance was measured at 540 nm. Nitrite and nitrate concentrations were calculated using a NaNO2 standard curve and expressed in micromolar.
Western ligand blot of IGFBP-3
Serum samples (2.5 µl) were subject to 1% SDS/12.5% acrylamide gel non-reducing electrophoresis, and electro-transferred to nitrocellulose membranes (HybondTM-C extra; Amersham Biosciences). The membranes were dried and blocked for 1 h with 5% non-fat dry milk/0.1% Tween (Sigma Chemical Co.), in Tris-buffered saline. Membranes were probed overnight at 4 °C with 125I-labelled IGF-I (5 x 105 c.p.m./ml). The nitrocellulose sheets were then washed, dried and blots were exposed at –80 °C to X-ray film (Kodak X-Omat AR; Eastman Kodak, Rochester, NY, USA) with two intensifying screens for 1–2 days depending on the signal obtained. Autoradiographs were analysed by densitometric scanning using a PC-Image VGA24 program (Foster Findlay Associates, Newcastle upon Tyne, UK) for Windows. The density of the IGFBP bands in each lane was expressed as the percentage of the mean density of sera from control rats injected with saline.
RNA extraction and Northern blot analysis
Total hypothalamic RNA was extracted by the guanidine thiocyanate method using a commercial kit (UltraspecTM RNA; Biotecx Laboratories, Houston, TX, USA), according to the protocol supplied by the manufacturer. For Northern blotting, 30 µg denatured RNA from each liver was separated by formaldehyde/agarose gel electrophoresis, transferred to nylon membranes (Hybond-N+; Amersham Biosciences) and fixed by UV crosslinking (Fotodyne, Hartland, WI, USA).
IGF-I and growth hormone receptor (GHR) mRNA hepatic levels were measured by Northern blot hybridization using riboprobes (Roberts et al. 1987, Baumbach et al. 1989). The rat IGF-I and GHR probes were derived from a HindIII fragment of the pGEM-3 plasmid vector (Promega). 32P-Labelled RNA antisense probes were generated from linearized plasmid with [-32P]CTP (Nuclear Ibérica, Madrid, Spain) and T7 RNA polymerase (Roche Molecular Biochemicals). Prehybridization was performed for 30 min at 68 °C in ULTRAhybTM buffer (Ambion, Austin, TX, USA) followed by hybridization for 16 h at the same temperature with 1 x 106 c.p.m./ml IGF-I-labelled riboprobe or 3 x 106 c.p.m./ml GHR-labelled riboprobe, in the same buffer.
The rat IGFBP-3 cDNA probe (Albiston & Herington 1990) was obtained by cutting the PEGEM 4Z plasmid vector using EcoRI and HindIII and labelling it with [32P]dCTP (Nuclear Ibérica, Madrid, Spain) by a random-priming DNA-labelling kit (DECAprimeTM II; Ambion). Prehybridization was performed for 30 min at 42 °C with ULTRAhybTM buffer followed by hybridization for 16 h at the same temperature with 3 x 106 c.p.m./ml IGFBP-3-labelled probe. To verify that equal amounts of RNA were loaded into each lane within an experimental group, control hybridization was performed with a 28 S DNA probe labelled with [32P]dCTP by random primer.
Statistical analysis
Statistics were computed using STATGRAPHICS plus for Windows. Statistical significance was calculated by multifactorial ANOVA with the LPS and gadolinium treatments as factors. When the ANOVA indicated a significant interaction between factors, individual means were compared by LSD multiple comparison test. A P value of less than 0.05 was considered significant.
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Results |
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, LPS administration induced a significant decrease (P < 0.01) in body-weight gain in control rats, whereas LPS did not modify body-weight gain in rats injected with gadolinium.
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. In control rats, LPS administration induced a significant decrease in serum concentrations of IGF-I (P < 0.01), in liver IGF-I (P < 0.01) and in the IGF-I gene expression in the liver (P < 0.05). Similar to the effects found in hepatic GHR mRNA, gadolinium pretreatment prevented the inhibitory effect of LPS on liver IGF-I, IGF-I mRNA and serum IGF-I levels (Fig. 3).
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), and gadolinium administration prevented the effect of LPS on liver IGFBP-3 mRNA. There was also a significant decrease (P < 0.01) in serum concentrations of IGFBP-3 in the control rats injected with LPS, whereas gadolinium administration blocked the effect of LPS on serum IGFBP-3 levels (Fig. 4).
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, LPS administration induced a significant increase in both ACTH and corticosterone serum levels (P < 0.01). Gadolinium pretreatment did not modify the serum concentrations of ACTH or corticosterone in control rats or in rats treated with LPS (Fig. 5).
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are shown in Fig. 6. Gadolinium pretreatment did not modify the serum concentrations of nitrites/nitrates, whereas LPS induced a significant increase (P < 0.01) in serum nitrite/nitrate levels in control rats, but not in the rats pretreated with gadolinium chloride. In the rats injected with saline, the serum concentrations of TNF- were undetectable. Gadolinium pretreatment did not modify TNF- release after LPS injection, since both control and rats pretreated with gadolinium had similar serum concentrations of TNF- (Fig. 6).
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Discussion |
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During sepsis, liver function is impaired and hepatocytes mainly synthesize acute-phase proteins, whereas constitutive protein synthesis is decreased in the liver. The inhibitory effect of LPS on liver IGF-I is well known. LPS is able to block the growth hormone-responsive genes in the liver of hypophysectomized rats (Bergard et al. 2000). In addition, cytokines and LPS are able to inhibit GHR and IGF-I gene expression both in vitro and in vivo (Wof et al. 1996, Defalque et al. 1999), suggesting that LPS induces GH resistance. Furthermore, LPS, at low doses, decreases liver IGF-I and IGFBP-3 gene expression in rats, whereas it stimulates GH secretion (Priego et al. 2003b). All these data indicate that one of the mechanisms by which LPS injection inhibits hepatic GHR, IGF-I and IGFBP-3 gene expression is by acting directly on the liver.
The greater decrease in serum concentrations of IGF-I and IGFBP-3 than in their mRNA in the liver can be due to modification in their half-life. IGFBP-3 is the major IGFBP in serum; the decrease in serum concentrations of IGFBP-3 may contribute to increasing IGF-I turnover and then to reducing IGF-I half-life in serum. The binary complexes form a ternary complexes with the acid-labile subunit, or ALS, and endotoxin administration also induces a decrease in serum concentrations of ALS (Barreca et al. 1998, Kong et al. 2002). Then the decrease in circulating IGFBP-3 and ALS might contribute to the decline in serum IGF-I observed after LPS administration.
Gadolinium treatment prevents liver injury after LPS by inhibiting superoxide production of large Kupffer cells (Kono et al. 2001), and completely prevents the increase in oxygen uptake due to endotoxin. Gadolinium pretreatment prevents iNOS induction by LPS in Kupffer cells (Roland et al. 1996, Hamada et al. 1999). This inhibitory effect on LPS-induced iNOS expression has also been reported in hepatocytes (Tirmenstein et al. 2000) and in other tissues such as the lung (Fujii et al. 1998). Thus the ability of gadolinium to prevent LPS-induced increase in serum concentrations of nitrite/nitrate can be the result of blocking iNOS induction in several tissues. We have previously observed that inhibition of iNOS by aminoguanidine treatment prevents LPS-induced decrease in IGF-I and IGFBP-3 gene expression in the liver (Priego et al. 2004). Therefore, prevention of iNOS induction and nitric oxide release in the liver may be one of the possible mechanisms by which gadolinium administration prevents the effect of LPS on serum and liver IGF-I and IGFBP-3.
It can be seen in our data that gadolinium administration also prevented an LPS-induced decrease in body weight. A decrease in serum concentrations of IGF-I is associated with negative nitrogen balance and hypermetabolism (Jeschke et al. 2005). In addition, IGF-I and IGFBP-3 administration increases protein synthesis in the skeletal muscle in burned humans (Debroy et al. 1999) and in septic rats (Svanberg et al. 2000). Taking into account that the IGF-I/IGFBP-3 system plays an important role in anabolic reactions, it is logical to think that, in the LPS-treated rats, the effects of gadolinium on body weight and on the IGF system are related.
In contrast to the IGF-I system, the stimulatory effect of LPS on ACTH and corticosterone secretion was not modified by gadolinium pretreatment. Cytokines and their receptors are expressed both in the hypothalamus and in the pituitary (Faggioni et al. 1995, Arzt et al. 1999). During inflammation, cytokines stimulate the hypothalamus-pituitary-adrenal axis, and upon increased corticosteroid secretion they antagonize their peripheral proinflammatory action (for review, see Chesnokova & Melmed 2002). In our study, gadolinium administration does not seem to affect cytokine release in tissues outside the liver, since it did not modify serum concentrations of TNF- after LPS injection. Similar results have previously been observed by other authors (Kohno et al. 1997, Rizzardini et al. 1998, Kono et al. 2001). Furthermore, Kono et al.(2002) have reported that although gadolinium administration prevented LPS-induced increase in TNF- gene expression in the liver, it did not modify the serum concentrations of TNF-. However, it has recently been reported that gadolinium treatment decreased superoxide generation, but conversely increased Kupffer cell TNF- production after LPS stimulation (Kinoshita et al. 2005). These data indicate that gadolinium treatment decreases phagocytosis and superoxide production in Kupffer cells, whereas its effect on TNF- and cytokine release is less clear.
It has been reported that depletion of macrophages did not prevent pituitary-adrenal activation after 2.5 mg/kg LPS administration (Derijk et al. 1991), suggesting that during LPS-induced sepsis, other mechanisms apart from macrophage-derived products are involved in the activation of the hypothalamus-pituitary-adrenal axis. These authors postulated that high doses of endotoxin may directly stimulate endothelial cells to produce cytokines and prostaglandin-E2 and thereby activate the hypothalamic-pituitary-adrenal axis in a macrophage-independent manner (Tilders et al. 1994).
Inactivation of Kupffer cells by gadolinium pretreatment is not able to prevent all the physiological reactions induced by LPS injection. It has previously been reported that gadolinium administration is not able to prevent the haemodynamic alterations of acute endotoxaemia (Fujii et al. 1998). Similarly, despite improved survival, gadolinium chloride failed to prevent laboratory and clinical signs of disseminated intravascular coagulation in endotoxaemic rats (Ruttinger et al. 1998).
On other hand, IGF-I has an important role in the early stages of liver tissue repair (Scharf et al. 2004). IGF-I administration results in effective prevention of lethal acute liver failure induced by D-galactosamine plus LPS treatment in rats (Inoue et al. 2003). For that reason, the therapeutic potential of IGF-I in the prevention of acute liver failure has been suggested. In addition, transgenic mice overexpressing IGF-I have attenuated fibrogenesis and accelerated liver regeneration after liver injury (Sanz et al. 2005).
Since the IGF-I system has been involved in tissue regeneration, these findings suggest that one of the possible mechanisms by which gadolinium prevents liver injury and metabolic derangement in septic rats is through normalization of the IGF-I system.
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Acknowledgements |
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Funding |
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References |
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Received in final form 7 December 2005
Accepted 21 December 2005
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