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At least 19 recordsLinked to original sources
PubMed1992

Interleukin 1 and its relationship to endotoxin tolerance.

Endotoxin (lipopolysaccharide [LPS])-induced cytokine release has been implicated in the pathogenesis of sepsis. Sublethal doses of LPS induce tolerance to a septic insult. This study evaluated pretreatment with interleukin 1 (IL-1) against an LPS challenge and examined its relationship to endotoxin tolerance. C3H/HeN mice (N = 100) were injected intraperitoneally with phosphate-buffered saline (control group), IL-1 (200 micrograms/kg), or LPS (1 mg/kg) for 3 days. On day 5, peritoneal macrophages were harvested and assayed for antimicrobial activity (superoxide anion production and Candida albicans phagocytosis). Serum cytokine levels and survival after an LPS challenge on day 5 were also assessed. Pretreatment with IL-1 or LPS significantly increased superoxide anion production, C albicans phagocytosis, and survival compared with pretreatment with phosphate-buffered solution. Interleukin 6 levels significantly decreased in the IL-1 and LPS groups. Peak levels of tumor necrosis factor significantly decreased only in the LPS group. Thus, pretreatment with IL-1 or low doses of LPS may exert protective effects by decreasing levels of interleukin 6 while increasing antimicrobial activity. Mice pretreated with IL-1 were protected from endotoxin despite elevated peak levels of tumor necrosis factor, suggesting a different mechanism for endotoxin tolerance than for tolerance to tumor necrosis factor.

Animals↗
PubMed1992

Endotoxin-inducible cytotoxicity in liver cell cultures--II. Demonstration of endotoxin-tolerance.

Endotoxins from gram negative bacteria, central mediators of septic shock, share the characteristic property of inducing tolerance against their own action. This work investigates whether a corresponding ex-vivo tolerance can be observed in a cellular system with endotoxin-inducible hepatocytoxicity. The following experimental approaches were chosen in order to induce an endotoxin-unresponsive state prior to cell preparation: (1) pretreatment of rats with endotoxin, (2) partial hepatectomy, (3) use of neonatal rats and (4) pretreatment of rats with silica. An in-vivo protection against endotoxin-induced liver injury was obtained by all of these four measures: cells prepared from these groups of animals showed greatly diminished sensitivity towards endotoxin-induced hepatocytotoxicity in vitro. The suppressed endotoxin sensitivity after silica pretreatment was partially restored in vitro by the addition of native Kupffer cells (KC). Isolated KC of all but the endotoxin-pretreated animals secreted tumor necrosis factor-alpha in response to endotoxin. It is concluded that different types of tolerance can be distinguished: (a) impairment of macrophage functions (silica pretreatment), (b) hepatocyte unresponsiveness (neonatal rats and hepatectomy) and (c) impaired macrophage function combined with hepatocyte unresponsiveness (endotoxin-pretreated rats).

Animals↗
PubMed1986

Endotoxin tolerance diminishes endotoxin-induced alterations in carbohydrate kinetics.

This study was designed to determine if attenuated mortality to a challenge dose of endotoxin was accompanied by or separated from alterations in glucose metabolism in endotoxin-tolerant rats. The in vivo effects of endotoxin were studied in catheterized endotoxin-tolerant rats and nontolerant control animals. Tolerance was induced by iv injections of 100 micrograms endotoxin/100 g BW (tolerance dose) for either 2 or 4 consecutive days; control rats received daily saline injections. On the day after the final tolerance dose, glucose kinetics were assessed by the constant infusion of [6-3H]-glucose prior to and after a challenge dose of endotoxin (1,000 micrograms/100 g) in tolerant and nontolerant rats. Following the challenge dose, 2-day tolerant animals exhibited an improved survival at 72 hr (LD 14 vs LD 92), a significantly smaller reduction in mean arterial blood pressure (20 vs 34%), and smaller increases in plasma glucose (9.4 +/- 0.6 vs 11.4 +/- 0.6 mM) and lactate (3.2 +/- 0.3 vs 8.5 +/- 1.4 mM) concentrations, compared to those in nontolerant control rats. However, increases in the rates of glucose appearance (Ra) and metabolic clearance (MCR) were not diminished. In 4-day tolerant rats, lethality to endotoxin was abolished, and no alterations in blood pressure or glucose kinetics were seen during the 4-hr period after endotoxin. However, the basal glucose Ra and MCR determined prior to endotoxin challenge were elevated in these rats compared to controls. Hyperglucagonemia was evident following the endotoxin challenge in control and 2-day tolerant rats, but not in 4-day tolerant animals. The hypothermia seen in nontolerant rats 4 hr after endotoxin was not present in either group of tolerant animals. The results show that after 2 days, tolerant animals have improved survival rates when challenged with endotoxin but still demonstrate acute changes in glucose kinetics. A complete protection against a normally lethal dose of endotoxin exists after 4 days. At this stage, rats showed no transient hemodynamic or metabolic alterations following endotoxin challenge.

Animals↗
PubMed1987

Glucose kinetics and development of endotoxin tolerance during long-term continuous endotoxin infusion.

Alterations in glucose metabolism are seen following the acute administration of lethal doses (LD) and nonlethal doses of endotoxin, but relatively little information is available concerning glucose kinetics during long-term continuous endotoxin infusion. A nonlethal dose of endotoxin was administered intravenously to catheterized rats for up to 54 hours via a subcutaneously implanted osmotic pump; time-matched control animals were saline-infused. Glucose kinetics were assessed in vivo after 6, 30, and 54 hours of endotoxin by the constant infusion of [6-3H, U-14C]-glucose. The endotoxemic animals were hemodynamically stable throughout the experimental protocol and exhibited a febrile response at six and 30 hours of endotoxin infusion. Elevations in glucose turnover (50% and 42%) and recycling (140% to 150%) were seen after six and 30 hours of endotoxin infusion, but had returned to control values by 54 hours. A major portion (53% to 62%) of the increased glucose turnover in endotoxemic rats was accounted for by the elevated rate of recycling. The increased turnover appeared to be almost entirely due to enhanced gluconeogenesis and is consistent with the 160% to 170% elevation in plasma glucagon and increased lactate availability. After 54 hours, the plasma concentrations of glucose and lactate, glucose kinetics, and body temperature were not different between endotoxemic and control animals. In separate groups of rats, a bolus injection of endotoxin (LD 100) was administered to determine the presence of endotoxin tolerance. Endotoxin-infused animals showed improved survival after 30 and 54 hours (LD 20 and LD 0).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Arachidonic acid turnover in peritoneal macrophages is altered in endotoxin-tolerant rats.

Peritoneal macrophages from endotoxin-tolerant rats have been found to exhibit depressed metabolism of arachidonic acid (AA) to prostaglandins and thromboxane in response to endotoxin. The effect of endotoxin tolerance on AA turnover in peritoneal macrophages was investigated by measuring [14C]AA incorporation and release from membrane phospholipids. Endotoxin tolerance did not affect the amount of [14C]AA incorporated into macrophages (30 min-24 h). However, the temporal incorporation of [14C]AA into individual phospholipid pools (15 min-24 h) was altered. In endotoxin-tolerant macrophages, [14C]AA incorporation into phosphatidylcholine (PC) (2, 4, 24 h) and phosphatidylethanolamine (PE) (8 h) was increased, while the incorporation into phosphatidylserine (PS) (2-24 h) was reduced (P less than 0.005) compared to control macrophages. There was no change in [14C]AA incorporation into phosphatidylinositol (PI). Following 2 or 24 h of incorporation of [14C]AA, macrophages were incubated (3 h) with endotoxin (50 micrograms/ml) or A23187 (1 microM), and [14C]AA release was measured. Endotoxin-tolerant macrophages released decreased (P less than 0.05) amounts of [14C]AA in response to both endotoxin and the calcium ionophore A23187 compared to controls. Control macrophages in response to endotoxin released [14C]AA from PC, PI and PE. In contrast, tolerant cells released [14C]AA only from PC (P less than 0.05). A23187 released [14C]AA from all four pools in the control cells, but only from PC and PE in the tolerant cells. These data demonstrate that endotoxin tolerance alters the uptake and release of AA from specific macrophage phospholipid pools. These results suggest that changes in AA turnover and/or storage are associated with endotoxin tolerance.

Animals↗
PubMed1990

Differential cytokine induction by doses of lipopolysaccharide and monophosphoryl lipid A that result in equivalent early endotoxin tolerance.

The phenomenon of early endotoxin tolerance, which is induced by sublethal injection of lipopolysaccharide (LPS), results in a protracted period of hyporesponsiveness that is most profound at 3 to 4 days after injection and is marked by reduced cytokine production after a challenge injection of LPS. Early endotoxin tolerance is also induced by the nontoxic LPS derivative monophosphoryl lipid A (MPL), although much more of the monophosphoryl derivative is required to produce a state of tolerance equivalent to that evoked by LPS. In this study, equivalent tolerance-inducing doses of LPS and MPL were tested, and the levels of cytokines induced by LPS and MPL were compared. Although induced levels of colony-stimulating factor were comparable following doses of LPS and MPL that elicited an equivalent state of early endotoxin tolerance, levels of tumor necrosis factor, interleukin-6, and interferon were significantly lower in MPL-injected animals. These results suggest that the lowered toxicity of MPL may be related to its elicitation of significantly lower levels of potentially toxic intermediaries such as tumor necrosis factor, interferon, and interleukin-6.

Animals↗
PubMed1992

Early endotoxin tolerance in suckling rats.

Early endotoxin tolerance has not been well investigated in the newborn. This study demonstrated that a sublethal dose of Salmonella enteritidis lipopolysaccharide (S. ent-LPS) or rough mutant Salmonella minnesota LPS (Re-LPS) induced early endotoxin tolerance in suckling rats, showing blunted hypoglycemia and decreased mortality. The mortality of endotoxic shock was lower in S. ent-LPS pretreated group than Re-LPS pretreated group. A sublethal dose of S. ent-LPS caused lactacidemia but Re-LPS did not. Therefore, early endotoxin tolerance appeared to be related to physiologic responses to the initial LPS exposure.

Animals↗
PubMed1988

Recombinant interleukin-1 alpha and recombinant tumor necrosis factor alpha synergize in vivo to induce early endotoxin tolerance and associated hematopoietic changes.

Endotoxin, the lipopolysaccharide (LPS) derived from gram-negative bacteria, invokes a wide range of responses in susceptible hosts. It is known that virtually all responses to LPS are mediated by the action of macrophage-derived cytokines (such as interleukin-1 [IL-1], tumor necrosis factor [TNF], and others) which are produced principally by macrophages and maximally within several hours of LPS administration. One manifestation of LPS administration which is not well understood is the phenomenon of "early endotoxin tolerance." In response to a single sublethal injection of LPS, experimental animals become refractory to challenge with a homologous or heterologous LPS preparation 3 to 4 days later. Animals rendered tolerant exhibit mitigated toxicity and a reduced capacity to produce circulating cytokines (i.e., colony-stimulating factor or interferon) in response to the challenge LPS injection. Previous studies have also shown that this state of transient, acquired hyporesponsiveness to LPS is accompanied by a marked increase in the size of cells in the bone marrow which are enriched in numbers of macrophage progenitors. In this study, we examined the capacity of recombinant IL-1 or recombinant TNF or both to induce early endotoxin tolerance and its associated hematopoietic changes. Neither cytokine alone was able to mimic LPS for induction of tolerance. Combined administration of recombinant IL-1 and recombinant TNF doses which were not toxic when administered individually led to synergistic toxicity (as assessed by death or weight loss). However, within a nontoxic range, the two cytokines synergized to induce a significant reduction in the capacity to produce colony-stimulating factor in response to LPS, as well as the characteristic increase in bone marrow cell size and macrophage progenitors shown previously to be associated with LPS-induced tolerance.

Animals↗
PubMed1992

Endotoxin tolerance is associated with altered GTP-binding protein function.

Previous studies have suggested that guanine nucleotide regulatory (G) proteins modulate endotoxin-stimulated peritoneal macrophage arachidonic acid (AA) metabolism. Endotoxin-stimulated metabolism of AA by peritoneal macrophages is decreased in endotoxin tolerance (Rogers et al. Prostaglandins 31: 639-650, 1986). These observations led to a study of G protein function and AA metabolism by peritoneal macrophages in endotoxin tolerance. Endotoxin tolerance was induced by the administration of sublethal doses of endotoxin. AA metabolism was assessed by measurement of thromboxane B2 (TxB2), a cyclooxygenase metabolite. NaF (5 mM), an activator of G proteins, significantly stimulated TxB2 synthesis in control macrophages from 7.7 +/- 0.2 to 19.1 +/- 0.6 (SE) ng/ml (P less than 0.05) at 2 h and was partially inhibited by pertussis toxin, suggesting a G protein-dependent mechanism. Salmonella enteritidis endotoxin (50 micrograms/ml) stimulated a similar increase in TxB2 levels (23 +/- 0.4 ng/ml, P less than 0.05). In contrast to control macrophages, macrophages from endotoxin-tolerant rats stimulated with either NaF or S. enteritidis endotoxin had TxB2 levels that were only 30 and 2% of the respective stimulated control cells. Basal guanosine-triphosphatase (GTPase) activity (33 +/- 6 pmol.mg-1.min-1) in endotoxin-tolerant macrophage membranes was significantly lower (P less than 0.05) than control basal activity (158 +/- 5 pmol.mg-1.min-1). This suppression of macrophage GTPase activity was apparent 48 h after the first in vivo sublethal endotoxin injection (100 micrograms/kg ip). The reduced GTPase activity paralleled in vitro cellular hyporesponsiveness to endotoxin-stimulated TxB2 production.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Endotoxin-tolerant rats are still protected from oxygen toxicity by low-dose endotoxin treatment.

To determine if we could reduce endotoxin's potential for toxicity, we produced "endotoxin-tolerant" rats by administering progressively increasing daily doses of endotoxin (10 ng, 100 ng, 1 microgram, 10 micrograms/kg). This dosage regimen produced a high degree of tolerance to the toxic actions of endotoxin: whereas only 3/17 (18%) of control rats survived a normally lethal dose of endotoxin (25 mg/kg), survival for the endotoxin-tolerant rats was 16/16. When endotoxin-tolerant rats received a standard protective dose of 500 micrograms/kg endotoxin just before transfer to 96-98% O2, 19/20 survived the 72-h exposure period vs. 20-30% survival for controls. Thus whereas the endotoxin-tolerant state blocked the tested lethal and toxic effects of endotoxin, it did not nullify the O2 protective action of endotoxin. In addition, endotoxin's stimulatory effects on the lung antioxidant enzymes in the 96-98% O2-exposed rats was also not blocked by the endotoxin-tolerant state. Thus the therapeutic ratio (TR) of endotoxin as an experimental pharmacological treatment against O2-induced lung damage has been markedly enhanced (TR = ratio of dose producing beneficial effects to dose producing toxic effects).

Acid Phosphatase↗
PubMed1987

Effect of endotoxin tolerance on drug hepatotoxicity: amelioration of taurolithocholate cholestasis in the perfused rat liver.

Induction of endotoxin tolerance may cause resistance not only to endotoxin itself but also to the hepatotoxic effects of other membrane-active agents. To further study this effect, we tested whether endotoxin tolerance could ameliorate the adverse effects of taurolithocholate (TLCA) which causes cholestasis by altering liver plasma membrane organization. Isolated perfused rat livers from endotoxin-tolerant rats had a lower basal bile flow than control livers. However, a bolus addition of TLCA at 3 X 10(-5) or 5 X 10(-5) M in the perfusate caused a marked and prolonged decrease of bile flow in controls, but only a transient and significantly less pronounced diminution of bile flow in endotoxin-tolerant livers. Likewise, TLCA caused a significantly lower alteration of hepatocyte membrane permeability, as measured by sucrose permeability studies, in endotoxin-tolerant livers than in controls. Analysis of bile acid composition of bile from endotoxin-tolerant livers demonstrated that they excreted greater amounts of total bile acids, in particular TLCA and taurocholate, than controls. These results demonstrated a protective effect of endotoxin-tolerance against TLCA toxicity which may result from an altered interaction of TLCA with liver membranes and an increased clearance of TLCA.

Animals↗
PubMed1991

Time course of IL-6 and TNF alpha release during endotoxin-induced endotoxin tolerance in rats.

Development of endotoxin tolerance in rats induced by repeated application of low dosages of endotoxin is associated with repeatable IL-6 formation, reversible drop in white blood cells, pronounced consumption of platelets, gradual formation of alpha 2M as an example of acute phase proteins, and flattening TNF alpha formation. In the status of full tolerance the TNF alpha release is completely eliminated. Inhibition of TNF alpha biosynthesis and induction of acute phase protein formation by IL-6 are discussed as possible factors in the development of endotoxin tolerance.

Acute-Phase Proteins↗
PubMed1976

Increased antibacterial activity against Escherichia coli in bovine serum after the induction of endotoxin tolerance.

Small amounts of endotoxin injected intramuscularly into cows induced endotoxin pyrogenic tolerance and an increase in the rate at which the serum killed a strain of Escherichia coli. Most of the difference between normal serum and serum from the endotoxin-tolerant animal was shown to be due to a bentonite-adsorbable factor other than lysozyme or beta-lysin. The antibacterial activity was not completely removed from either type of serum after bentonite adsorption. Electron microscope studies and measurement of the rate of release of radioactively labeled cytoplasmic contents showed that the bentonite-adsorbable factor was important in the final breakdown of the cell membrane and release of cellular contents. The antibacterial system was totally dependent on complement, and the importance of antibodies could not be entirely ruled out because adsorption at O C with homologous cells eliminated the killing activity.

Adsorption↗
PubMed2026

Acyloxyacyl Hydrolase-Mediated Lipopolysaccharide Inactivation Limits Macrophage Endotoxin Tolerance and Promotes Inflammation and Fibrosis in Metabolic Dysfunction-Associated Steatohepatitis.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis, a chronic liver disease, is characterized by persistent low-grade inflammation, partially driven by gut-derived lipopolysaccharide. Although repeated lipopolysaccharide exposure can induce endotoxin tolerance in innate immune cells, its role in chronic liver diseases remains unclear. Acyloxyacyl hydrolase is an endogenous enzyme that inactivates lipopolysaccharide, potentially modulating this process. We aimed to investigate how acyloxyacyl hydrolase regulates endotoxin tolerance in Kupffer cells and how this affects hepatic inflammation and fibrosis during metabolic dysfunction-associated steatohepatitis progression. METHODS: Acyloxyacyl hydrolase-deficient mice and wild-type controls were subjected to multiple dietary metabolic dysfunction-associated steatohepatitis models. Inflammatory responses, fibrosis, and transcriptomic changes in liver tissues and isolated Kupffer cells were analyzed. Endotoxin tolerance was modulated through β-glucan administration or lipopolysaccharide preconditioning. Lipopolysaccharide bioactivity was assessed using Toll-like receptor 4-reporter cell assays. RESULTS: Lipopolysaccharide-preconditioned Kupffer cells exhibited reduced proinflammatory cytokine production and transcriptional suppression of inflammatory pathways, indicating tolerance. Despite slight elevation of plasma lipopolysaccharide levels in metabolic dysfunction-associated steatohepatitis, upregulation of hepatic acyloxyacyl hydrolase positively correlated with disease severity, suggesting enhanced lipopolysaccharide inactivation but impaired establishment of tolerance. In contrast, acyloxyacyl hydrolase-deficient Kupffer cells displayed reinforced endotoxin tolerance, leading to diminished hepatic inflammation and fibrosis. Reversal of tolerance using β-glucan reactivated inflammatory and fibrogenic responses in acyloxyacyl hydrolase-deficient mice, whereas tolerance induction by low-dose lipopolysaccharide preconditioning mitigated metabolic dysfunction-associated steatohepatitis pathology, supporting the protective role of macrophage tolerance in chronic liver injury. CONCLUSIONS: Endotoxin tolerance in Kupffer cells represents a protective mechanism against chronic liver inflammation and fibrosis. Acyloxyacyl hydrolase regulates this state by limiting bioactive lipopolysaccharide, thereby modulating the establishment of endotoxin tolerance and downstream inflammatory and fibrotic responses. Enhancing macrophage tolerance by utilizing lipopolysaccharide may offer a novel therapeutic avenue to control the progression of metabolic dysfunction-associated steatohepatitis.

AOAH↗
PubMed1990

Altered responses to modulators of guanine nucleotide binding protein activity in endotoxin tolerance.

The effects of cholera toxin or pertussis toxin and nonhydrolyzable GTP analogs on Salmonella enteritidis endotoxin stimulation of iTxB2 and i6-keto-PGF1 alpha synthesis in control and endotoxin tolerant rat peritoneal macrophages were determined. Pretreatment with pertussis toxin alone had no effect on basal macrophage iTxB2 or i6-keto-PGF1 alpha production, but pertussis toxin (0.1, 1.0 and 10 ng/ml) significantly inhibited endotoxin-stimulated iTxB2 and i6-keto-PGF1 alpha synthesis. Pretreatment with cholera toxin, which did not affect basal iTxB2 or i6-keto-PGF1 alpha synthesis, significantly enhanced endotoxin-induced synthesis of iTxB2 and i6-keto-PGF1 alpha. The effects of pertussis and cholera toxin with or without endotoxin were significantly (P less than 0.05) less in macrophages from endotoxin tolerant rats compared to control macrophages. GTP[gamma-S] (100 microM) significantly increased iTxB2 synthesis and significantly augmented endotoxin-stimulated iTxB2 synthesis in control macrophages (P less than 0.05). However, in macrophages from endotoxin tolerant rats the effect of GTP[gamma-S] on iTxB2 synthesis was significantly less (P less than 0.05) compared to control macrophages. Collectively, these data suggest that: (1) guanine nucleotide binding regulatory proteins mediate endotoxin-stimulated arachidonic acid metabolism in rat peritoneal macrophages; and (2) endotoxin tolerance induces alterations in guanine nucleotide binding protein activity.

Animals↗
PubMed1975

The nature of endotoxin tolerance.

Certain of the mechanisms by which man develops pyrogenic tolerance to bacterial endotoxins have been considered. After an initial intravenous injection of toxin, two temporally distinct phases of tolerance can be discerned, early and late, each with very different characteristics. Early tolerance appears to be mediated by a non-antibody mechanism entailing a transiently occurring refractory state, apparently involving to a major degree decreased production of endogenous pyrogen by the macrophage system, particularly the hepatic macrophages. Late tolerance appears to be mediated by anti-endotoxin antibodies directed against both "O" and common core antigens which blunt the release of endogenous pyrogen from macrophages. The common core antigens are masked in the presence of the "O" antigenic side chains and become effective immunogens only when these "O" side chains are lacking. Accelerated reticuloendothelial system clearance of circulating endotoxin provides an ancillary protective mechanism in that it brings the toxin more efficiently into the macrophages that are refractory or protected by antibody. When endotoxin is administered repeatedly at closely spaced intervals, both the early phase (non-immune) and late phase (immune) mechanisms may become superimposed. In addition, a third mechanisms, enhanced detoxification capabilities of macrophages, also now appears to come into play. At any given time, it is the relative contribution of each mechanism, which in turn is dependent upon the immunization schedule, antigenicity of the endotoxin, dosage, and immunological competency of the host, that determines the expression of the endotoxin tolerant state.

Antibody Formation↗