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High in vitro endotoxin responsiveness of macrophages from an endotoxin-resistant wild rodent species, Sigmodon
C B Dabbert1, R L Lochmiller, J R Zhang
1Department of Zoology, Oklahoma State University, Stillwater 74078.
Abstract:
It has been reported that macrophages primarily mediate endotoxin shock and cell death by synthesizing and releasing cytokines, largely tumor necrosis factor (TNF) and interleukin-1 (IL-1). However, macrophages from some laboratory mouse strains such as C3h/HeN are unresponsive to endotoxin both in vivo and in vitro. We found members of a wild rodent species, Sigmodon hispidus, to also be extremely resistant to bacterial endotoxin challenge. Intravenous administration of up to 100,000 micrograms/kg body mass of Escherichia coli O26:B6 endotoxin did not cause lethality in adult S. hispidus. In contrast to the endotoxin-resistant mouse strain, peritoneal macrophages derived from S. hispidus were responsive to in vitro endotoxin challenge as measured by high levels of TNF and IL-1 activity in supernatants of macrophage cultures. Thus, in vitro macrophage responsiveness to endotoxin does not always indicate high host sensitivity to endotoxin challenge.
Insights
Wild rodents, Sigmodon hispidus, show extreme resistance to endotoxin shock. Their macrophages respond to endotoxin in vitro, but the host remains resistant, challenging the link between macrophage sensitivity and host endotoxin tolerance.
Area of Science:
- Immunology
- Toxicology
- Animal Physiology
Background:
- Macrophages are key mediators of endotoxin shock via cytokine release (TNF, IL-1).
- Some mouse strains exhibit endotoxin unresponsiveness, both in vivo and in vitro.
- Understanding differential endotoxin responses is crucial for sepsis and inflammation research.
Purpose of the Study:
- To investigate the endotoxin resistance of the wild rodent species, Sigmodon hispidus.
- To determine if in vitro macrophage responsiveness correlates with in vivo endotoxin tolerance in S. hispidus.
- To explore the mechanisms underlying differential endotoxin sensitivity.
Main Methods:
- Administered high doses of Escherichia coli O26:B6 endotoxin intravenously to adult S. hispidus.
- Assessed host lethality following endotoxin challenge.
- Cultured peritoneal macrophages from S. hispidus and stimulated them with endotoxin in vitro.
- Measured tumor necrosis factor (TNF) and interleukin-1 (IL-1) activity in macrophage culture supernatants.
Main Results:
- S. hispidus demonstrated extreme resistance to endotoxin challenge, with no lethality observed even at 100,000 µg/kg body mass.
- Peritoneal macrophages from S. hispidus were responsive to in vitro endotoxin stimulation.
- High levels of TNF and IL-1 activity were detected in supernatants of endotoxin-stimulated S. hispidus macrophages.
Conclusions:
- In vitro macrophage responsiveness to endotoxin does not necessarily predict in vivo host sensitivity.
- Sigmodon hispidus serves as a model for studying mechanisms of endotoxin resistance.
- Further research is needed to elucidate the physiological basis for S. hispidus's remarkable endotoxin tolerance.