HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0803041v1 183/5/3309    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Holub, M. Articles by Gregory, S. H. PubMed PubMed Citation Articles by Holub, M. Articles by Gregory, S. H.

Neutrophils Sequestered in the Liver Suppress the Proinflammatory Response of Kupffer Cells to Systemic Bacterial Infection¹

Martin Holub^*, Chao-Wen Cheng^*, Stephanie Mott^*, Philip Wintermeyer^*, Nico van Rooijen and Stephen H. Gregory^2,*

^* Department of Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown University Providence, RI 02903; and Department of Cell Biology, Vrije Universiteit, Amsterdam, The Netherlands

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-1β, IL-6, IL-10, IL-12, TNF-, MIP-1, keratinocyte-derived chemokine, and MCP-1 mRNA levels were 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-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health Research Grant DK068097 and funds provided by Rhode Island Hospital. Purchase and operation of FACSAria were supported by National Center for Research Resources Shared Instrumentation Grant 1S10RR021051-01A2.

² Address correspondence and reprint requests to Dr. Stephen H. Gregory, Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School at Brown University, 432 Pierre M. Galletti Building, 55 Claverick Street, Providence, RI 02903. E-mail address: sgregory{at}lifespan.org

³ Abbreviations used in this paper: NPC, nonparenchymal liver cell; Cl₂MDP-L, liposome-encapsulated dichloromethylene diphosphonate; KC, keratinocyte-derived chemokine; MPO, myeloperoxidase; 7-AAD, 7-aminoactinomycin D.