Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GH treatment can increase the mortality and morbidity of critically ill patients. The mechanisms of these harmful effects of GH are unknown but have been, in part, ascribed to interactions between GH and the immune system. Because GH has pattern-dependent actions we have now compared the dose-related effects of continuous and intermittent GH treatment given with or without an endotoxin (lipopolysaccharide; LPS) challenge. Male Wistar rats (n=6 per group) were treated for 5 days with recombinant human GH (0, 10, 100 or 1000 microg/kg per day) using either continuous s.c. infusion by osmotic minipump or intermittent twice daily s.c. injections. On day 4, endotoxin (5 mg/kg, i.p.) was injected and the animals monitored for a further 16 h. LPS administration alone led to neutrophilia and lymphopoenia, with increased plasma concentrations of urea, cholesterol, triglyceride, insulin and leptin, and decreased levels of IGF-I. High dose GH infusion (1000 microg/kg per day) followed by LPS caused greater increases in plasma urea, cholesterol, triglyceride, sodium and magnesium, but lower plasma glucose and insulin levels, than treatment with LPS alone. In contrast, twice daily injections of GH did not enhance these effects of endotoxin. In conclusion, the effects of endotoxin on plasma electrolytes, lipids, urea, glucose and insulin are differentially affected by the pattern of GH administration in the rat.
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PMID:The metabolic effects of endotoxin are differentially affected by the pattern of GH administration in the rat. 1157 1

The aim of this work was to elucidate the possible role of glucocorticoids in the bacterial lipopolysaccharide (LPS)-induced decrease in hepatic IGF-I synthesis. For this purpose, we studied the effect of LPS on IGF-I in two rat strains, Wistar and Lewis, which have different adrenal responses to inflammation. Compared with Wistar rats, Lewis rats have a reduced hypothalamic-pituitary-adrenal response to inflammatory stimuli. Rats received two i.p. injections of 1 mg/kg LPS and were killed 4 h after the second injection. LPS induced an increase in serum concentrations of both ACTH and corticosterone, the increase being more pronounced in Wistar than in Lewis rats. LPS decreased hepatic GH receptor (GHR) and IGF-I mRNA only in Wistar rats. However, serum concentrations of IGF-I were significantly decreased (P<0.01) in both Wistar and Lewis rats. These data indicate that the adrenal axis may mediate the inhibitory effect of LPS on GHR and IGF-I synthesis in the liver. In a second experiment, adrenalectomized or sham-operated Wistar rats were injected with LPS. Two LPS injections (0.1 mg/kg) decreased serum concentrations of IGF-I in both type of rat; however, the inhibitory effect of LPS on liver GHR and IGF-I mRNA was observed in adrenalectomized rats, but not in intact rats. All these data suggest that some component of the adrenal axis, other than glucocorticoids, mediates the inhibitory effect of LPS on liver GHR and IGF-I.
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PMID:Glucocorticoids are not necessary for the inhibitory effect of endotoxic shock on serum IGF-I and hepatic IGF-I mRNA. 1187 93

We studied the IGFBP-3 response to endotoxin, in Wistar and Lewis rats. Compared to Wistar rats, Lewis rats have a reduced adrenal and IGF-I response to inflammatory stimuli. Rats received two injections of 1 mg/kg of lipopolysaccharide (LPS) and were killed 4 h after the second injection. LPS decreased serum concentrations of GH in Wistar (P<0.05), but not in Lewis rats. However, serum IGFBP-3 was decreased both in Wistar and in Lewis rats. Furthermore, LPS administration decreased IGFBP-3 gene expression in the liver in both rat strains (P<0.01). Lewis rats had lower serum IGFBP-3 than Wistar rats (P<0.01). This difference could be secondary to the increased IGFBP-3 proteolysis in serum observed in Lewis rats. These data indicate that acute inflammation inhibits serum concentrations of IGFBP-3 by decreasing its synthesis in the liver, rather than increasing its proteolysis. This effect seems to be GH and IGF-I independent.
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PMID:Endotoxin decreases serum IGFBP-3 and liver IGFBP-3 mRNA: comparison between Lewis and Wistar rats. 1258 76

Sepsis and endotoxin (LPS or lipopolysaccharide) injection induce a state of growth hormone (GH) resistance leading to decreased circulating insulin-like growth factor (IGF)-I. Because the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta inhibit the GH-stimulated IGF-I expression in vitro, it was tempting to speculate that these two cytokines might play an important role in the reduction of circulating IGF-I levels caused by LPS. Pentoxifylline, a methylxanthine usually used in the treatment of peripheral arterial circulatory disorders, has been reported to inhibit TNF-alpha synthesis. The goal of our study was to investigate whether inhibition of TNF-alpha production by pentoxifylline could prevent the decrease in IGF-I and the GH resistance caused by LPS injection. Because previous studies demonstrated that pentoxifylline can reduce muscle catabolism induced by sepsis, we also assessed whether pentoxifylline could exert its anticatabolic effect by preventing the decrease in circulating IGF-I. LPS injection in rats decreased serum IGF-I (-45% at 12 h; P<0.01 vs time 0) and its liver mRNA (-67% at 12 h; P<0.01 vs time 0) while it induced circulating TNF-alpha and IL-1beta and their hepatic expression (P<0.01). Pretreatment of LPS-treated animals by pentoxifylline abolished the LPS-induced rise in serum TNF-alpha (-98% at 90 min; P<0.001 vs LPS alone) and to a lesser extent in serum IL-1beta (-44% at 3 h; not significant vs LPS alone). Despite its dramatic inhibitory effect on TNF-alpha induction, however, pentoxifylline failed to suppress both the decrease in IGF-I and the GH resistance induced by LPS in rats. These results suggest that mediators other than TNF-alpha, in particular IL-1beta or IL-6, could contribute to the GH resistance induced by LPS. They also suggest that the anticatabolic effect of pentoxifylline is not due to prevention of the decline of circulating IGF-I.
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PMID:Inhibition of TNF-alpha production by pentoxifylline does not prevent endotoxin-induced decrease in serum IGF-I. 1284 41

While it is well known that sepsis inhibits serum IGF-I and its gene expression in the liver, the effect on pituitary GH and IGF-binding protein-3 (IGFBP-3) is poorly understood. The GH-IGF-I-IGFBP-3 response to different doses of lipopolysaccharide (LPS) administration has been investigated in adult male rats. Two experiments were performed, administration of low doses of LPS (5, 10, 50 and 100 microg/kg) and high doses of LPS (100, 250, 500 and 1000 microg/kg). Rats received two i.p. injections of LPS (at 1730 h and 0830 h the following day) and were killed 4 h after the second injection. LPS administration induced a biphasic response in serum concentrations of GH, with an increase at the 10 microg/kg dose, followed by a decrease at higher doses (100 microg/kg on up). Pituitary GH mRNA was also increased by the administration of 10 and 50 microg/kg LPS, whereas at higher doses LPS did not modify pituitary GH mRNA. We also analyzed the GH response to LPS in primary pituitary cell cultures. When exposed to LPS, in the culture medium, there was an increase in GH release at the concentration of 0.1 and 10 ng/ml, whereas more concentrated LPS did not modify GH release. Serum concentrations of IGF-I declined in a dose-dependent fashion after LPS administration in the rats injected with 10 microg/kg LPS on up. This decrease is secondary to modifications in its synthesis in the liver, since endotoxin injection decreased both IGF-I and its mRNA in the liver. The liver GH receptor mRNA was also decreased by LPS administration, but only in the animals injected with high LPS doses. There was a decrease in both the IGFBP-3 serum levels and its gene expression in the liver with all LPS doses studied. These data suggest a biphasic LPS effect on pituitary GH, a stimulatory effect at low doses and an inhibitory effect at higher doses, whereas it has a clear inhibitory effect on IGF-I and IGFBP-3 synthesis in the liver. The decrease in liver IGFBP-3 mRNA and in serum concentrations of IGFBP-3 in the rats injected with LPS may contribute to the decrease in serum concentrations of IGF-I.
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PMID:Endotoxin at low doses stimulates pituitary GH whereas it decreases IGF-I and IGF-binding protein-3 in rats. 1452 71

Seventy-two crossbred pigs (7.58 +/- 0.30 kg BW) weaned at 28 +/- 3 d of age were used to investigate the effects of fish oil supplementation on pig performance and on immunological, adrenal, and somatotropic responses following an Escherichia coli lipopolysaccharide (LPS) challenge in a 2 x 2 factorial design. The main factors consisted of diet (7% corn oil [CO] or 7% fish oil [FO]) and immunological challenge (LPS or saline). On d 14 and 21, pigs were injected intraperitoneally with either 200 microg/kg BW of LPS or an equivalent amount of sterile saline. Blood samples were collected 3 h after injection for analysis of interleukin-1beta (IL-1beta), prostaglandin E2 (PGE2), cortisol, growth hormone (GH), and insulin-like growth factor (IGF)-I. On d 2 after LPS challenge, peripheral blood lymphocyte proliferation (PBLP) was determined. Lipopolysaccharide challenge decreased ADG (487 vs. 586 g; P < 0.05) and ADFI (as-fed, 776 vs. 920 g; P < 0.05) from d 14 to 21 and ADG (587 vs. 652 g; P < 0.10) from d 21 to 28. Fish oil improved ADG (554 vs. 520 g; P < 0.10) and ADFI (891 vs. 805 g; P < 0.10) from d 14 to 21. On d 14, LPS challenge x diet interactions were observed for IL-1beta (P < 0.10), PGE2 (P < 0.001), and cortisol (P < 0.05) such that these measurements responded to the LPS challenge to a lesser extent (IL-1beta: 93 vs. 114 pg/mL, P < 0.05; PGE2: 536 vs. 1,285 pg/mL, P < 0.001; cortisol: 143 vs. 206 ng/mL, P < 0.05) in pigs receiving the FO diet than in pigs fed the CO diet. In contrast, among LPS-treated pigs, pigs fed the FO diet had higher IGF-I (155 vs. 101 ng/mL; P < 0.10) than those fed the CO diet. On d 21 among LPS-treated pigs, pigs fed FO had lower IL-1beta (70 vs. 84 pg/mL; P < 0.10) and cortisol (153 vs. 205 ng/mL; P < 0.05) than those fed CO. Pigs fed FO had lower PGE2 (331 vs. 444 pg/mL; P < 0.05) and higher IGF-I (202 vs. 171 ng/mL; P < 0.10) compared with those fed CO. Lipopolysaccharide challenge decreased GH (0.27 vs. 0.33 ng/mL; P < 0.05) on d 14, whereas it had no effect on GH on d 21. During both LPS challenge periods, the challenge increased PBLP when these cells were incubated with 8 (1.46 vs. 1.32; P < 0.10) or 16 microg/mL (1.46 vs. 1.30; P < 0.05) of concanavalin A. Fish oil had no effect on PBLP. These results suggest that FO alters the release of proinflammatory cytokines, which might lead to improved pig performance during an immunological challenge.
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PMID:Effects of fish oil supplementation on the performance and the immunological, adrenal, and somatotropic responses of weaned pigs after an Escherichia coli lipopolysaccharide challenge. 1460 79

Although the interleukin (IL)-1 receptor is densely distributed in the leptomeninges constituting the blood/cerebrospinal fluid barrier, its physiologic significance has remained unclear. In the present study, we show that in cultured leptomeningeal cells, IL-1beta, tumor necrosis factors, or lipopolysaccharide causes a prominent increase in the synthesis and release of prostaglandin (PG) D synthase, which catalyzes the final step in the biosynthesis of PGD2. Although significant increases in the amount of PGD synthase were also observed with cells exposed to somatostatin, thrombin, or ciliary neurotrophic factor, these were much smaller than were those induced by the proinflammatory cytokines. Other agents tested including IGF-I had no effect upon the enzyme levels in the culture media. Furthermore, we found that the increased secretion of PGD synthase by IL-1beta was completely inhibited by 10(-7) M PGE2. The same dose of PGD2 or 15-deoxy-Delta(12-14)PGJ2 had no effect upon the IL-1beta action. In addition, PGE2 increased the level of fibronectin and eliminated the expression of zonula occludentes-1, a tight junction-associated protein from cultured cells, effects likely reflecting a loss of barrier integrity. These results demonstrate the importance of inflammatory stimuli as a physiologic regulator of the leptomeningeal cell function.
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PMID:Effects of interleukin-1beta and prostaglandin E2 on prostaglandin D synthase production in cultivated rat leptomeningeal cells. 1508 10

There is vast body of evidence that the insulin-like growth factor (IGF)-I exerts immunomodulatory effects in vitro and in vivo. In vitro studies indicate that stimulatory effects of IGF-I may be exerted through augmentation of inflammatory cytokine production. To further explore the immunomodulatory effects of IGF-I through regulation of cytokine production, we tested the in vitro effects of IGF-I on the secretion of inflammatory T helper cell type 1 (Th1) and Th2 cytokines by human peripheral blood mononuclear cells (PBMC). To this end, PBMC were stimulated with the T cell mitogen phytohemagglutinin (PHA), and cytokines in the culture media were assessed after 18, 42, 66, and 80 h of culture. We found that IGF-I stimulated the secretion of the Th2 cytokine interleukin (IL)-10 by 40-70% in PHA-stimulated PBMC. In addition, we observed a small stimulatory effect (15%) on the secretion of another Th2 cytokine IL-4. The secretion of IL-2, IL-5, IL-6, interferon-gamma, and the inflammatory cytokines IL-1beta, IL-8, and tumor necrosis factor alpha was not or was hardly affected. IL-10 secretion was also stimulated in purified T cells, and we established that IGF-I also stimulated IL-10 mRNA expression by 100-150%. The monocyte-activating bacterial cell-wall product lipopolysaccharide induced IL-10 production in PBMC, but this was not affected by IGF-I. As IL-10 predominantly exerts anti-inflammatory actions and suppresses Th1-dependent immune responses, our results indicate that IGF-I may exert inhibitory actions on inflammatory and Th1-mediated cellular immune responses through stimulation of IL-10 production in T cells.
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PMID:Insulin-like growth factor-I stimulates IL-10 production in human T cells. 1527 70

Endotoxin (i.e., lipopolysaccharide, LPS) impairs skeletal muscle protein synthesis. Although this impairment is not acutely associated with a decreased plasma concentration of total amino acids, LPS may blunt the anabolic response to amino acids. To examine this hypothesis, rats were injected intraperitoneally with LPS or saline (Sal) and 4 h thereafter were orally administered either leucine (Leu) or Sal. The gastrocnemius was removed 20 min later to assess signaling components important in the translational control of protein synthesis. In the Sal-Leu group phosphorylation of 4E-BP1 in muscle was markedly increased, compared to values from time-matched saline-treated control rats. This change was associated with a redistribution of eukaryotic initiation factor (eIF) 4E from the inactive eIF4E x 4E-BP1 complex to the active eIF4E x eIF4G complex. In LPS-treated rats, the Leu-induced phosphorylation of 4E-BP1 and changes in eIF4E distribution were partially or completely abrogated. LPS also antagonized the Leu-induced increase in phosphorylation of S6K1, ribosomal protein S6 and mTOR. Neither LPS nor leu altered the total amount or phosphorylation of TSC2 in muscle. The ability of LPS to blunt the anabolic effects of Leu could not be attributed to differences in the plasma concentrations of insulin or Leu between groups. Furthermore, the replacement of plasma insulin-like growth factor (IGF)-I in LPS-treated rats to basal levels also did not ameliorate the defect in leucine-induced phosphorylation of S6K1 or S6, although it did reverse the LPS-induced decrease in the constitutive phosphorylation of mTOR, S6 and 4E-BP1. Pretreatment with the glucocorticoid receptor antagonist RU486 was unable to prevent the LPS-induced leucine resistance. In contrast, to the abovementioned results with leucine, LPS did not prevent the ability of pharmacological levels of IGF-I to phosphorylate 4E-BP1, S6K1, mTOR or alter the availability of eIF4E. Hence, LPS working via a glucocorticoid-independent mechanism produces a leucine resistance in skeletal muscle that might be expected to impair the ability of this amino acid to stimulate translation initiation and protein synthesis.
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PMID:Endotoxin disrupts the leucine-signaling pathway involving phosphorylation of mTOR, 4E-BP1, and S6K1 in skeletal muscle. 1538 31

Infections direct amino acids away from growth and skeletal muscle accretion toward the hepatic synthesis of acute-phase proteins. The loss of skeletal muscle protein stores results in both a decrease in muscle function and an increase in mortality. In general, muscle protein synthesis is decreased in rodent models of sepsis, as well as after the injection of components of the bacterial cell wall, such as lipopolysaccharide. Although the overexpression of proinflammatory cytokines is known to hasten the loss of skeletal muscle protein, it is not known whether this represents a direct effect of cytokines or results from secondary changes in the IGF system. Plasma concentrations of IGF-I are dramatically lowered by infection in rats, mice, pigs, and steers. The drop in IGF-I often occurs despite an increase in the plasma concentration of somatotropin. Animals are therefore considered to be GH resistant. The IGF bioactivity is determined not only by the plasma concentration of the ligand, but also by IGFBP; IGFBP-3 is the most abundant of these binding proteins and undergoes proteolysis during some catabolic states. In contrast to IGFBP-3, the plasma concentration of inhibitory IGFBP, such as IGFBP-1, is increased during infection. Insulin-like growth factor-binding protein-1 accumulates in skeletal muscle, where it can potentially inhibit IGF-dependent protein synthesis. Insulin-like growth factor-I and IGFBP-1 are regulated at the level of gene transcription by proinflammatory cytokines. Recent studies demonstrate that bacterial components that activate immune cells also activate the innate immune response in skeletal muscle. Lipopolysaccharide increases proinflammatory cytokine messenger RNA expression in muscle from control mice, but not from mice with a mutation in the lipopolysaccharide receptor. Lipopolysaccharide also increases cytokine expression in human and mouse myoblasts. Local expression of cytokines in skeletal muscle may negatively regulate the autocrine synthesis of IGF-I. Current work is focused on deciphering the mechanism by which muscle becomes GH resistant and the development of therapies to maintain muscle protein stores during infection.
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PMID:Alteration of somatotropic function by proinflammatory cytokines. 1547 89


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