Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis

Shinji Shimoda, Kenichi Harada, Hiroaki Niiro, Ken Shirabe, Akinobu Taketomi, Yoshihiko Maehara, Koichi Tsuneyama, Yasuni Nakanuma, Patrick Leung, Aftab A. Ansari, M. Eric Gershwin, Koichi Akashi

Research output: Contribution to journalArticle

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Abstract

Primary biliary cirrhosis (PBC) is characterized by chronic nonsuppurative destructive cholangitis (CNSDC) associated with destruction of small bile ducts. Although there have been significant advances in the dissection of the adaptive immune response against the mitochondrial autoantigens, there are increasing data that suggest 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 (TLRs), 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 alpha (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. Conclusion: These data highlight critical differences in the varied roles of Mo and NK cells following TLR3-L and TLR4-L stimulation.

Original languageEnglish
Pages (from-to)1270-1281
Number of pages12
JournalHepatology
Volume53
Issue number4
DOIs
Publication statusPublished - Apr 1 2011

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Biliary Liver Cirrhosis
Toll-Like Receptors
Bile Ducts
Natural Killer Cells
Ligands
Toll-Like Receptor 4
Monocytes
Liver
Interferon-alpha
Epithelial Cells
Toll-Like Receptor 3
Autoantigens
Adaptive Immunity
Ligation
Dissection
Hepatocytes
Observation
Pathology

All Science Journal Classification (ASJC) codes

  • Hepatology

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Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis. / Shimoda, Shinji; Harada, Kenichi; Niiro, Hiroaki; Shirabe, Ken; Taketomi, Akinobu; Maehara, Yoshihiko; Tsuneyama, Koichi; Nakanuma, Yasuni; Leung, Patrick; Ansari, Aftab A.; Gershwin, M. Eric; Akashi, Koichi.

In: Hepatology, Vol. 53, No. 4, 01.04.2011, p. 1270-1281.

Research output: Contribution to journalArticle

Shimoda, S, Harada, K, Niiro, H, Shirabe, K, Taketomi, A, Maehara, Y, Tsuneyama, K, Nakanuma, Y, Leung, P, Ansari, AA, Gershwin, ME & Akashi, K 2011, 'Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis', Hepatology, vol. 53, no. 4, pp. 1270-1281. https://doi.org/10.1002/hep.24194
Shimoda, Shinji ; Harada, Kenichi ; Niiro, Hiroaki ; Shirabe, Ken ; Taketomi, Akinobu ; Maehara, Yoshihiko ; Tsuneyama, Koichi ; Nakanuma, Yasuni ; Leung, Patrick ; Ansari, Aftab A. ; Gershwin, M. Eric ; Akashi, Koichi. / Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis. In: Hepatology. 2011 ; Vol. 53, No. 4. pp. 1270-1281.
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