Neutrophils Sequestered in the Liver Suppress the Proinflammatory Response of Kupffer Cells to Systemic Bacterial Infection

Abstract

The liver plays a major role in clearing bacteria from the bloodstream. Rapid clearance is primarily the function of fixed tissue macrophages (Kupffer cells) that line the hepatic sinusoids. Although Kupffer cells play a critical role in blood clearance, the actual elimination of the bulk of bacteria taken up by the liver depends upon the accumulation of bactericidal neutrophils. Subsequent experiments demonstrating neutrophils inside Kupffer cells derived from infected animals prompted our speculation that neutrophils modulate the proinflammatory response of Kupffer cells to bacteria cleared from the bloodstream. Indeed, we report here that neutrophils accumulated in the liver sinusoids suppress cytokine and chemokine mRNA expression and protein production by Kupffer cells. Using listeriosis in mice as an experimental model, we found that IL-1beta, IL-6, IL-10, IL-12, TNF-alpha, MIP-1alpha, keratinocyte-derived chemokine, and MCP-1 mRNA levels were >or=10-fold more in the livers of Listeria-infected, relative to noninfected control, mice at 0.5-2 h after i.v. infection. Most message levels were sharply diminished thereafter, correlating inversely with increased neutrophil sequestration. Relative to intact animals, mice rendered neutrophil deficient exhibited marked increases in cytokine/chemokine mRNA expression and protein production in the liver subsequent to infection. Moreover, purified Kupffer cells derived from infected, neutrophil-depleted mice produced significantly more IL-6, IL-10, IL-12, TNF-alpha, keratinocyte-derived chemokine, and MCP-1 in culture. These findings document the critical role of neutrophils in moderating the proinflammatory response of Kupffer cells to bacteria taken up by the liver.