Glucocorticoid Regulation of Hepatic TNF Production Following Cecal Ligation and Puncture Sepsis

Zawacki, Jeffrey K.; Hunt, J.; Gamelli, Richard L.; Filkins, James P.

doi:10.1097/00024382-199708000-00014

Cited by 9 publications

(4 citation statements)

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“…In contrast, chronic treatment with dexamethasone for 15 days inhibited TNF-␣ expression in immortalized human pre-adipocytes in line with the immunosuppressive action of glucocorticoids [123] . Consistent with these data, glucocorticoids have been shown to inhibit TNF-␣ production in several animal models [124] , while adrenalectomy causes elevated TNF-␣ levels during a septic insult in rats [125] .…”

Section: Tnf-␣ and The Hpa Axissupporting

confidence: 65%

Adipokines and Cardiovascular Risk in Cushing’s Syndrome

et al. 2011

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Cushing’s syndrome (CS) is associated with increased cardiovascular morbidity and mortality. Recent evidence also suggests that increased cardiovascular risk may persist even after long-term remission of CS. Increased central obesity, a typical feature of CS, is associated with altered production of adipokines, which contributes to the pathogenesis of several metabolic and cardiovascular complications observed in this condition. In vitro and in vivo studies have shown a relationship between cortisol and adipokines in several experimental settings. In patients with either active or ‘cured’ CS, an increase in leptin and resistin levels as well as the release of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, may be associated with increased cardiovascular risk. For other adipokines, including adiponectin, results are inconclusive. Studies are needed to further elucidate the interactions between clinical and subclinical increases in cortisol production and altered adipokine release in CS.

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Section: Tnf-␣ and The Hpa Axissupporting

confidence: 65%

Adipokines and Cardiovascular Risk in Cushing’s Syndrome

et al. 2011

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“…Hence, RU486 treatment of septic rats potentially unmasks or accentuates inhibitory effects of other mediators, such as TNFα. In this regard, RU486 increases the early sepsisinduced increase in NF-κB activation in muscle (40) and increases cytokine production in septic or endotoxemic animals (41,42). Collectively, these findings are consistent with reports that adrenalectomized rats and intact rats treated with RU486 are more susceptible to the lethal effects of endotoxin, sepsis, IL-1, and TNFα (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoids and TNFα Interact Cooperatively to Mediate Sepsis-Induced Leucine Resistance in Skeletal Muscle

Lang

Frost

2006

Mol Med

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Sepsis blunts the ability of nutrient signaling by leucine to stimulate skeletal muscle protein synthesis by impairing translation initiation. The present study tested the hypothesis that overproduction of either tumor necrosis factor (TNF)-α or glucocorticoids mediate the sepsis-induced leucine resistance. Prior to producing peritonitis, rats received either vehicle, TNF binding protein (TNF BP ) to inhibit endogenous TNFα action, and/or the glucocorticoid receptor antagonist RU486. Leucine was orally administered to all rats 24 h thereafter and the gastrocnemius removed 20 min later to assess protein synthesis and signaling components important in controlling peptide-chain initiation. Muscle protein synthesis was 65% lower in septic rats administered leucine than in leucinetreated control animals. This reduction was not prevented by either TNF BP or RU486 alone, but was completely reversed by the combination. This sepsis-induced leucine resistance was associated with an 80% reduction in the amount of active eIF4E·eIF4G complex, a 5-fold increase in the formation of the inactive eIF4E·4E-BP1 complex as well as markedly reduced (at least 70%) phosphorylation of 4E-BP1, eIF4G, S6K1, S6, and mTOR. Pretreatment of septic rats with either TNF BP or RU486 individually only nominally improved the leucine action as assessed by the above-mentioned endpoints. In contrast, when TNF BP and RU486 were co-administered, the ability of sepsis to impair the leucine-stimulated phosphorylation of 4E-BP1, eIF4G, S6K1, and S6 as well as the redistribution of eIF4E was essentially prevented. No differences in the total amount or phosphorylation of eIF2α and eIF2Bε were detected between the different groups, and changes could not be attributed to differences in the prevailing plasma concentration of insulin or leucine. Our data demonstrate the sepsis-induced leucine resistance in skeletal muscle results from the cooperative interaction of both TNFα and glucocorticoids.

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“…While the differences in the profiles of TNF-␣ in serum between E. coli-and S. aureus-infected animals correlate with the observed differences in mortality in the D-galactosamine model (40) (Table 1), they also raise the question of whether Finally, there is increasing concern about possibly important differences in host inflammatory responses to sepsis due to gram-positive versus gram-negative bacteria (11,17,32), including recent reexamination of the scope and limitation of glucocorticoids to address such concerns (3,27,39,40,46; D. G. Remick, Editorial, Shock 8:146, 1997). The present findings contribute to our growing knowledge base of differences in host responses to different classes of bacteria and the still further differences resulting from specific antibiotic chemotherapy and, ultimately, should lead to greater harmony between complementary modes of anti-inflammatory and antibiotic intervention strategies.…”

Section: Discussionmentioning

confidence: 99%

Differential Host Inflammatory Responses to Viable Versus Antibiotic-Killed Bacteria in Experimental Microbial Sepsis

Silverstein¹,

Wood

Xue

et al. 2000

Infect Immun

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Staphylococcus aureus killed during imipenem or ceftazidime chemotherapy in mice elicited an early release of tumor necrosis factor alpha (TNF-␣) into the systemic circulation. This response was coincident in time with an increase in leukocyte-endothelium adhesive interactions in the microvasculature. Equivalent responses were not observed without the antibiotic treatment (imipenem or ceftazidime). Protective efficacy of the same antibiotic treatment was markedly diminished in D-galactosamine-treated mice compared to controls; e.g., it dropped from 2,000-fold to 70-fold with 4 mg of imipenem per kg given at the time of challenge. Nevertheless, protection was quantitatively restored upon concurrent administration of neutralizing anti-TNF-␣ antibody or 4 mg of dexamethasone per kg to these TNF-␣-hypersensitive mice. Importantly, protection afforded by dexamethasone was not seen when the animals were challenged with viable organisms but without the concurrent administration of antibiotic. An early TNF-␣ response could also be demonstrated upon challenge with Escherichia coli, but in this instance, neither the timing nor the magnitude of that response was influenced by treatment with these antibiotics. We conclude from these studies that the inflammatory response to viable versus killed bacteria may differ markedly depending on the particular bacterium, host sensitivity to TNF-␣, and possibly the Gram stain classification.

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Glucocorticoid Regulation of Hepatic TNF Production Following Cecal Ligation and Puncture Sepsis

Cited by 9 publications

References 0 publications

Adipokines and Cardiovascular Risk in Cushing’s Syndrome

Adipokines and Cardiovascular Risk in Cushing’s Syndrome

Glucocorticoids and TNFα Interact Cooperatively to Mediate Sepsis-Induced Leucine Resistance in Skeletal Muscle

Differential Host Inflammatory Responses to Viable Versus Antibiotic-Killed Bacteria in Experimental Microbial Sepsis

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