The Interaction Between Toll Like Receptors and Natural Killer Cells in the Destruction of Bile Ducts in Primary Biliary Cirrhosis

• Authors: Shinji Shimoda, Kyushu University; Kenichi Harada, Kanazawa University; Hiroaki Niiro, Kyushu University; Ken Shirabe, Kyushu University; Akinobu Taketomi, Kyushu University; Yoshihiko Maehara, Kyushu University; Koichi Tsuneyama, University of Toyama; Yasuni Nakanuma, Kanazawa University; Patrick Leung, University of California; Aftab A Ansari, Emory University; M. Eric Gershwin, University of California; Koichi Akashi, Kyushu University
• Journal Title: Hepatology
• Volume: Volume 53, Number 4
• Publisher: Wiley-Blackwell | 2011-04, Pages 1270-1281
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/hep.24194
• Subjects: Health Sciences, Medicine and Surgery; Health Sciences, Pathology
• Keywords: natural killer cells; monocytes; biliary epithelial cells; toll-like receptors; IFN-α; primary biliary cirrhosis

Abstract

Primary biliary cirrhosis (PBC) is characterized by chronic non-suppurative destructive cholangitis (CNSDC) associated with destruction of small bile ducts. Although there have been significant advancements in the dissection of the adaptive immune response against the mitochondrial autoantigens, there is increasing data that suggests a contribution of innate immune mechanisms in inducing chronic biliary pathology. We have taken advantage of our ability to isolate subpopulations of liver mononuclear cells (LMC) and examined herein the role of toll-like receptors (TLR), their ligands and natural killer (NK) cells in modulating cytotoxic activity against biliary epithelial cells (BECs). In particular, we demonstrate that toll-like receptor 4 ligand (TLR4-L) stimulated NK cells destroy autologous BECs in the presence of interferon (IFN)-α synthesized by TLR 3 ligand (TLR3-L) stimulated monocytes (Mo). Indeed, IFN-α production by hepatic Mo is significantly increased in patients with PBC compared to disease controls. There were also marked increases in the cytotoxic activity of hepatic NK cells from PBC patients compared to NK cells from controls but only when the NK cells were prepared following ligation of both TLR3-L and TLR4-L stimulated LMC. These functional data are supported by the immunohistochemical observation of an increased presence of CD56 positive NK cells scattered around destroyed small bile ducts more frequently in liver tissues from PBC patients than controls. In conclusion, these data highlight critical differences in the varied roles of Mo and NK cells following TLR3-L and TLR4-L stimulation.