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The role of IFN-gamma in the pathology of experimental endotoxemia
1Department of Medicine, University of California San Francisco Medical Center 94143.
Abstract:
Proinflammatory cytokines provoked by circulating bacterial LPS mediate many of the destructive host responses characteristic of septic shock. To determine if the lymphokine IFN-gamma has a similar pathogenic role during endotoxic shock, mice were pretreated with murine rIFN-gamma (rMuIFN-gamma) at various times relative to challenge with Salmonella enteritidis LPS. Subsequent mortality was increased when rMuIFN-gamma was administered before or up to 4 h after endotoxin challenge. Pretreatment with rMuIFN-gamma resulted in nearly fivefold increases in serum TNF during endotoxemia, but TNF levels were unaffected by IFN administered after endotoxin. The increased levels of serum TNF probably reflected enhanced translation of this factor, as tissue expression of TNF mRNA did not increase correspondingly in IFN-pretreated mice. To examine the role of IFN-gamma produced endogenously during endotoxemia, mice were pretreated with 0.5 mg of anti-IFN-gamma mAb before endotoxin injection. This treatment significantly reduced mortality from endotoxic shock but caused only minor decreases in serum TNF. Anti-IFN-gamma administered 2 h after endotoxin was similarly protective. These results demonstrate a significant role for IFN-gamma in the pathology of septic shock, both indirectly as an activator of monokines known to promote lethality and possibly by other, late-acting mechanisms.
Insights
Interferon-gamma (IFN-γ) exacerbates septic shock by increasing tumor necrosis factor (TNF) and potentially through other mechanisms. Blocking IFN-γ reduces mortality, highlighting its pathogenic role in endotoxic shock.
Area of Science:
- Immunology
- Pathophysiology
- Molecular Biology
Background:
- Septic shock involves destructive host responses mediated by proinflammatory cytokines, such as lipopolysaccharide (LPS).
- The role of interferon-gamma (IFN-γ) in the pathogenesis of endotoxic shock requires further elucidation.
Purpose of the Study:
- To investigate the pathogenic role of IFN-γ in endotoxic shock.
- To determine the effect of exogenous and endogenous IFN-γ on mortality and cytokine levels during LPS-induced shock.
Main Methods:
- Mice were pretreated with recombinant murine IFN-γ (rMuIFN-γ) or anti-IFN-γ monoclonal antibody (mAb) at various times relative to challenge with Salmonella enteritidis LPS.
- Serum levels of tumor necrosis factor (TNF) and mortality rates were assessed.
Main Results:
- Pretreatment with rMuIFN-γ increased mortality and serum TNF levels when administered before or up to 4 hours after LPS challenge.
- IFN-γ administration after LPS challenge did not affect TNF levels.
- Endogenous IFN-γ blockade with anti-IFN-γ mAb significantly reduced mortality from endotoxic shock, irrespective of administration timing.
- Anti-IFN-γ mAb treatment caused only minor decreases in serum TNF.
Conclusions:
- IFN-γ plays a significant role in the pathology of septic shock.
- IFN-γ contributes to lethality indirectly by activating monokines like TNF and potentially through other late-acting mechanisms.