Toll-like receptor 2 contributes to liver injury by Salmonella infection through Fas ligand expression on NKT cells in mice

doi:10.1053/gast.2002.36006

Gastroenterology

Volume 123, Issue 4, October 2002, Pages 1265-1277

https://doi.org/10.1053/gast.2002.36006 Get rights and content

Abstract

Background & Aims: Toll-like receptors (TLRs) for bacterial constitutes are expressed not only by phagocytes but also by some subsets of T cells. We previously reported that natural killer T cells (NKT cells) play an important role in liver injury induced by Salmonella infection. In the present study, we investigated whether TLRs on NKT cells are involved in Salmonella-induced liver injury. Methods: Gene expression of TLR2 was examined in sorted natural killer, NKT, and T cells from livers of naive mice by the reverse-transcription polymerase chain reaction method. Serum alanine aminotransferase level and FasL expression on liver lymphocytes were examined in TLR2-deficient (TLR2^−/−) and FasL-deficient gld/gld mice before and after intraperitoneal inoculation of Salmonella choleraesuis 31N-1 using an enzyme-linked immunosorbent assay and flow cytometry. Results: TLR2 gene was abundantly expressed by NKT cells freshly isolated from naive mice. FasL expression on liver NKT cells increased in TLR2^+/− mice but not in TLR2^−/− mice after Salmonella infection. Serum alanine aminotransferase level was significantly lower in the TLR2^−/− and gld/gld mice than in the control mice after infection. Conclusions: TLR2 may contribute to liver injury induced by Salmonella infection via FasL induction on liver NKT cells.

GASTROENTEROLOGY 2002;123:1265-1277

Section snippets

Mice and microorganisms

Seven- to 8-week-old female C57BL/6 (B6) wild-type (wt), gld/gld (gld) with B6 background, C3H/HeN, and C3H/HeJ mice were purchased from Japan SLC, Inc. (Hamamatsu, Japan). The mutant mouse (F2 interbred from 129/Ola × C57BL/6) strain deficient in TLR2 was generated by gene targeting as described previously.²⁵ Age- and sex-matched groups of TLR2^−/− mice and their littermate (TLR2^+/−) mice were used for the experiments. In some experiments, siblings from the same mother were used. All of the

Expressions of TLRs in mouse intrahepatic lymphocyte subsets

We previously reported that a significant fraction of mouse T lymphocytes expressed TLR2.29, 30 We first examined the expressions of TLR genes on intrahepatic lymphocyte subsets, including NK, NKT, and T cells, that had been purified from naive B6 mice by cell sorting. Total RNA was extracted from each population, and the expression of TLR2, TLR4, TLR5, and TLR9 genes was analyzed by semiquantitative reverse-transcription PCR. As shown in Figure 1, TLR2, TLR4, and TLR5 mRNAs were detected in

Discussion

We have previously shown that NKT cells play a critical role in liver injury induced by Salmonella infection using Jα281 knockout mice.¹⁹ However, the precise molecular requirements for the NKT cell–mediated liver injury in Salmonella infection remain unknown. We showed that FasL expression on NKT cells was markedly elevated in vivo after Salmonella infection. FasL was constitutively expressed on NKT cells and other cells without liver injury, so modest further increases alone clearly might not

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^☆: Supported in part by grants from the Japanese Ministry of Education, Science and Culture, JSPS-RFTF97L00703, Yamada Science Foundation, Yasuda Medical Research Foundation, and Yakult Bioscience Foundation.

^☆☆: Address requests for reprints to: Tetsuya Matsuguchi, M.D., Ph.D., Laboratory of Host Defense and Germfree Life, Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. e-mail: [email protected]; fax: (81) 52-744-2449.

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Basic–Liver, Pancreas, and Biliary TractToll-like receptor 2 contributes to liver injury by Salmonella infection through Fas ligand expression on NKT cells in mice☆,☆☆

Abstract

Section snippets

Mice and microorganisms

Expressions of TLRs in mouse intrahepatic lymphocyte subsets

Discussion

Lancet

Hepatology

J Hepatol

Cell

Immunity

Genomics

Blood

Microb Pathog

Gastroenterology

Gastroenterology

Hepatology

J Biol Chem

Mol Cell

J Biol Chem

J Biol Chem

Hepatology

Hepatology

J Hepatol

Hepatology

Salmonella hepatitis

J Gastroenterol Hepatol

Biochemistry of endotoxins

Annu Rev Biochem

Involvement of NK1+ T cells and their IFN-gamma production in the generalized Shwartzman reaction

J Immunol

The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag+ T cells in T helper 1 immune responses

Immunol Rev

Plasma tumor necrosis factor alpha predicts decreased long-term survival in severe alcoholic hepatitis

Alcohol Clin Exp Res

IL-18 accounts for both TNF-alpha- and Fas ligand-mediated hepatotoxic pathways in endotoxin-induced liver injury in mice

J Immunol

Dominant expression of a distinctive V14+ T-cell antigen receptor alpha chain in mice

Proc Natl Acad Sci U S A

Predominant expression of invariant V alpha 14+ TCR alpha chain in NK1.1+ T cell populations

Int Immunol

Mouse CD1-specific NK1 T cells: development, specificity, and function

Annu Rev Immunol

CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides

Science

Selective ability of mouse CD1 to present glycolipids: alpha-galactosylceramide specifically stimulates V alpha 14+ NK T lymphocytes

J Immunol

Basic–Liver, Pancreas, and Biliary Tract
Toll-like receptor 2 contributes to liver injury by Salmonella infection through Fas ligand expression on NKT cells in mice☆,☆☆