The Journal of Experimental Medicine
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Published online January 14, 2008
doi:10.1084/jem.20072195
The Journal of Experimental Medicine, Vol. 205, No. 1, 233-244
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Tu et al.
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ARTICLE

 TLR-dependent cross talk between human Kupffer cells and NK cells

Zhengkun Tu1, Adel Bozorgzadeh1, Robert H. Pierce3, Jonathan Kurtis4, I. Nicholas Crispe2, and Mark S. Orloff1

1 Department of Surgery, Division of Solid Organ Transplantation and Hepatobiliary Surgery and 2 David H. Smith Centerfor Vaccine Biology and Immunology, University of Rochester Medical Center, Rochester, NY 14642
3 Experimental Pathology and Pharmacology, Schering-Plough Biopharma, Palo Alto, CA 94304
4 Center for International Health Research, Department of Pathology and Laboratory Medicine, Rhode Island Hospital,Brown University, Providence, RI 02903

CORRESPONDENCE Mark S. Orloff: mark_orloff{at}urmc.rochester.edu

The liver protects the host from gut-derived pathogens yet is tolerant of antigenic challenge from food and commensal sources. Innate responses involving liver macrophages (Kupffer cells) and effector liver natural killer (NK) cells form the first line in this defense. We address the impact of Toll-like receptor (TLR) signaling on the cross talk between these two cells, and reveal how the liver displays a down-regulated inflammatory response to constitutive bacterial elements through the secretion of interleukin (IL) 10 yet retains a vigorous response to viral challenge. The data support the model that (a) human liver Kupffer cells respond to TLR ligands and indirectly activate NK cells; (b) the activation depends on cell–cell contact; (c) the Kupffer cells synthesize NK cell activating signals, among which IL-18 is critical, and NK cell inhibitory factors, including IL-10; (d) ligands that signal via myeloid differentiation factor 88 induce IL-10, giving a blunted response in the NK cells; and (e) ligands that signal via the Toll–IL-1 receptor domain–containing adaptor inducing interferon (IFN) β–IFN regulatory factor 3 pathway induce less IL-10, and also directly potentiate the stimulatory effect of IL-18 on NK cells, resulting in enhanced activation. Subversion of cellular mechanisms of innate immune response against viruses may be important for hepatotropic viruses (e.g., hepatitis B and C) to develop persistence.

Abbreviations used: CBA, cytokine bead assay; HCV, hepatitis C virus; IRF-3, IFN regulatory factor 3; LMNC, liver mononuclear cell; LTA, lipoteichoic acid; MyD88, myeloid differentiation factor 88; NKG2D, NK receptor G2D; PAMP, pathogen-associated molecular pattern; poly I:C, polyinosinic:polycytodylic acid; TLR, Toll-like receptor; TRIF, Toll–IL-1 receptor domain–containing adaptor inducing IFN-β.


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