Prednisolone Dose-Dependently Influences Inflammation and Coagulation during Human Endotoxemia

Abstract

The effects of steroids on the outcome of sepsis are dose dependent. Low doses appear to be beneficial, but high doses do not improve outcome for reasons that are insufficiently understood. The effects of steroids on systemic inflammation as a function of dose have not previously been studied in humans. To determine the effects of increasing doses of prednisolone on inflammation and coagulation in humans exposed to LPS, 32 healthy males received prednisolone orally at doses of 0, 3, 10, or 30 mg (n = 8 per group) at 2 h before i.v. injection of Escherichia coli LPS (4 ng/kg). Prednisolone dose-dependently inhibited the LPS-induced release of cytokines (TNF-α and IL-6) and chemokines (IL-8 and MCP-1), while enhancing the release of the anti-inflammatory cytokine IL-10. Prednisolone attenuated neutrophil activation (plasma elastase levels) and endothelial cell activation (von Willebrand factor). Most remarkably, prednisolone did not inhibit LPS-induced coagulation activation, measured by plasma concentrations of thrombin-antithrombin complexes, prothrombin fragment F1+2, and soluble tissue factor. In addition, activation of the fibrinolytic pathway (tissue-type plasminogen activator and plasmin-α2-antiplasmin complexes) was dose-dependently enhanced by prednisolone. These data indicate that prednisolone dose-dependently and differentially influences the systemic activation of different host response pathways during human endotoxemia.

Inhibition of monocyte-derived inflammatory cytokines by IL-25 occurs via p38 Map kinase–dependent induction of Socs-3

“…These cytokines play a pivotal role in LPS-induced endotoxic shock, and inhibition of the LPSinduced cascade of proinflammatory cytokines is the primary mechanism through which anti-inflammatory molecules confer protection against the lethal effects of LPS administration. [31][32][33] In line with this, we showed that IL-25 pretreatment protected animals from the LPS-induced death. Importantly, the therapeutic effect of IL-25 in this model was associated with no significant change in the production of Th2-and Th17-related cytokines (ie, IL-4 and IL-17A, respectively), thus arguing against the hypothesis that some of the negative effects of IL-25 on the course of LPS-mediated endotoxemia are indeed due to its ability to either promote Th2-or inhibit Th17-associated cell responses.…”

Prototypical anti-inflammatory cytokine IL-10 prevents loss of IGF-I-induced myogenin protein expression caused by IL-1β

“…Whereas high concentrations of recombinant IL-10 up to 300 ng/ml are commonly used for in vitro and ex vivo experiments (5,20,28,31,38,59), the in vitro endogenous expression of IL-10 rarely exceeds 1 ng/ml, even when cells are stimulated with high concentrations of LPS (100 -1,000 ng/ml) (24,47). Similarly, endogenous IL-10 concentration is even lower in plasma of humans afflicted with various diseases, such as malaria (15) and human African trypanosomiasis (11), or in healthy males injected with 4 ng/kg LPS (13). We utilized a low, more physiologically relevant concentration of IL-10 (10 ng/ml) to evaluate how it regulates IL-1␤-induced signaling activity in myoblasts.…”

In Vivo Lipopolysaccharide Exposure of Human Blood Leukocytes Induces Cross-Tolerance to Multiple TLR Ligands

“…The volunteers were challenged (at t ϭ 0) with LPS (Escherichia coli LPS, lot G; U.S. Pharmacopeia) as a bolus i.v. injection at a dose of 4 ng/kg body weight as previously described (32)(33)(34). Blood was collected from a cannulated forearm vein directly before LPS administration (t ϭ 0) and at 1, 2, 3, 4, 6, 8, and 24 h thereafter.…”