Dioxin alters inflammatory responses to lipopolysaccharide

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has well characterized effects on specific immune responses, but the effects on the innate immune system are less understood. The effect of TCDD on inflammatory responses induced by lipopolysaccharide (LPS) was evaluated in C57BL/6J female mice. Mice were treated with 30 µg kg⁻¹ TCDD or vehicle once, p.o., and 4 days later, animals received LPS (0.05 × 10⁷ EU kg⁻¹, i.p.) or vehicle. Inflammatory mediators and the liver injury marker, alanine aminotransferase (ALT), were measured, and liver histology was evaluated. TCDD-treated animals had higher plasma ALT activity than vehicle-treated animals, but the effect was mild and time-dependent. Few changes in liver histopathology were observed, mainly represented in greater steatosis in TCDD/LPS-treated mice compared to mice treated with LPS or TCDD alone. LPS produced a time-dependent increase in the plasma concentrations of interleukins (IL)-6, -10, and -12 and interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein (MCP)-1. With the exception of IL-12, concentrations of each of these mediators were higher in plasma of mice co-treated with TCDD and LPS compared to either agent alone. The dose–response curve for the concentration of IL-6 in plasma suggested that dioxin increased the potency of LPS to cause the release of this cytokine but not the maximal response. Co-treatment with TCDD and LPS also led to greater expression of mRNA for IL-10 and IFN-γ compared to either TCDD or LPS alone. These results suggest that TCDD changes the inflammatory cytokine profile induced by LPS and that LPS enhances the hepatic steatotic response to TCDD.

Keywords:

• inflammation
• TCDD
• endotoxin
• cytokines

Acknowledgments

This study was supported by the National Institutes of Health, National Institute of Environmental Health Sciences [Grant ES004911]. Jesus Olivero-Verbel was supported in part by the Postdoctoral Training Program of Colciencias (2006–2007), Bogotá, Colombia, and the University of Cartagena, Cartagena, Colombia.