Inhibition of concanavalin A-induced hepatic injury of mice by bacterial lipopolysaccharide via the induction of IL-6 and the subsequent reduction of IL-4: the cytokine milieu of concanavalin A hepatitis

Nishikage, Tetsuro; Seki, Shu; Toyabe, Shin-ichi; Abo, Toru; Kagata, Yutaka; Iwai, Takehisa; Hiraide, Hoshio

doi:10.1016/s0168-8278(99)80159-7

Cited by 27 publications

(32 citation statements)

References 31 publications

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“…Until recently, Con A-induced hepatitis was considered a Th1-mediated disease model (6 -10, 16). However, recently several reports have revealed that IL-4, a Th2 cytokine that is elevated in the liver following Con A injection, exhibits proinflammatory effects during Con A-induced hepatitis as demonstrated by anti-IL-4 Ab or IL-4 gene-deficient mice studies (12,15,17). For this reason, we evaluated whether the exaggerated hepatic injury seen after CCL2/ MCP-1 neutralization in Con A-treated mice could be attributed to overproduction of hepatic IL-4.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, CD1d gene-deficient and ␤ 2 -microglobulin gene-deficient mice express very few NKT cells (11,15,(45)(46)(47), and these mice are resistant to Con A-induced hepatitis (11,12,15). A wealth of recent evidence demonstrates a regulatory role for resident hepatic NKT cells in augmenting hepatic damage via the secretion of IL-4 during Con A-induced hepatitis (12,15,17). Specifically, Kaneko et al (15) demonstrated that IL-4 produced by Con A-activated resident hepatic NK1.1 ϩ T cells acts on NK1 ϩ T cells in an autocrine fashion to induce the up-regulation of Fas ligand (FasL) expression on these cells, ultimately resulting in an enhancement of NK1.1 ϩ T cell-mediated cytotoxicity (12,15,17).…”

Section: Discussionmentioning

confidence: 99%

“…A wealth of recent evidence demonstrates a regulatory role for resident hepatic NKT cells in augmenting hepatic damage via the secretion of IL-4 during Con A-induced hepatitis (12,15,17). Specifically, Kaneko et al (15) demonstrated that IL-4 produced by Con A-activated resident hepatic NK1.1 ϩ T cells acts on NK1 ϩ T cells in an autocrine fashion to induce the up-regulation of Fas ligand (FasL) expression on these cells, ultimately resulting in an enhancement of NK1.1 ϩ T cell-mediated cytotoxicity (12,15,17). Therefore, the possibility that the suppression of NKT cell-derived IL-4 may play a direct and crucial role in the anti-inflammatory effects of CCL2/MCP-1 during Con A-induced hepatitis was investigated.…”

Section: Discussionmentioning

confidence: 99%

“…ϩ NK1.1 ϩ T cells in vitro IL-4 has been shown to play a direct proinflammatory role in Con A-induced hepatitis (12,15,17). Moreover, IL-4 appears to be derived almost exclusively from activated resident hepatic NKT cells after Con A administration (15).…”

Section: Ccl2/mcp-1 Inhibits Il-4 Production and Decreases Ccr2 Exprementioning

confidence: 99%

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C-C Chemokine Ligand 2/Monocyte Chemoattractant Protein-1 Directly Inhibits NKT Cell IL-4 Production and Is Hepatoprotective in T Cell-Mediated Hepatitis in the Mouse

Ajuebor

Hogaboam

et al. 2003

The Journal of Immunology

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T cell-mediated liver diseases are associated with elevated serum levels of C-C chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1). However, the extent to which the actions of CCL2/MCP-1 contribute to the pathogenesis of T cell-mediated hepatitis remains incompletely understood. Con A-induced hepatitis is a liver-specific inflammation mediated by activated T cells and is driven by an up-regulation of the hepatic expression of TNF-α, IFN-γ, and IL-4. The present study examined the role of CCL2/MCP-1 in the pathogenesis of T cell-mediated hepatitis induced by Con A administration in the mouse. We demonstrate a novel hepatoprotective role for CCL2/MCP-1 during Con A-induced hepatitis, because CCL2/MCP-1 neutralization strikingly enhanced hepatic injury, both biochemically and histologically, after Con A administration. Furthermore, CCL2/MCP-1 neutralization was associated with a significant reduction in the hepatic levels of TNF-α and IFN-γ, but with a significant increase in hepatic IL-4 levels. Moreover, IL-4 production and CCR2 expression by Con A-stimulated CD3+NK1.1+ T cells was significantly reduced by rMCP-1 treatment in vitro. In summary, we propose that CCL2/MCP-1 fulfills a novel anti-inflammatory role in T cell-mediated hepatitis by inhibiting CD3+NK1.1+ T cell-derived IL-4 production through direct stimulation of its specific receptor CCR2. These findings may have direct clinical relevance to T cell-mediated hepatitis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ccl2/mcp-1 Inhibits Il-4 Production and Decreases Ccr2 Exprementioning

confidence: 99%

See 2 more Smart Citations

C-C Chemokine Ligand 2/Monocyte Chemoattractant Protein-1 Directly Inhibits NKT Cell IL-4 Production and Is Hepatoprotective in T Cell-Mediated Hepatitis in the Mouse

Ajuebor

Hogaboam

et al. 2003

The Journal of Immunology

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“…IL-4 (often considered the major Th2-driving cytokine), along with GM-CSF or IFN-␥, enhances the production of bioactive IL-12 heterodimer and selectively reduces production of the antagonistic IL-12 p40 homodimer by DC (55). This can explain why Con A-induced liver injury is IL-4 as well as IL-12 dependent (12,13,56). The DC-NKT cell interaction initiated by ␣GalCer binding to CD1d on DC can thus trigger a cascade in which the production of IL-12 (by IL-4) and its bioactivity (by IL-18) are strikingly amplified.…”

Section: Discussionmentioning

confidence: 99%

Activating Immunity in the Liver. I. Liver Dendritic Cells (but Not Hepatocytes) Are Potent Activators of IFN-γ Release by Liver NKT Cells

Trobonjača

Leithäuser

Möller

et al. 2001

The Journal of Immunology

105

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A prominent subset of the hepatic innate immune system is α-galactosylceramide (αGalCer)-reactive, (CD4+ and CD4−CD8−) CD1d-restricted NKT cells. We investigated in C57BL/6 (B6) mice which hepatic cell type stimulates hepatic NKT cell activation. Surface expression of CD1d but not CD40, CD80, or CD86 costimulator molecules was detected in hepatocytes. Pulsed in vitro or in vivo with αGalCer, hepatocytes triggered IL-4 release by liver NKT cells but required exogenous IL-12 to trigger IFN-γ release by NKT cells. Liver dendritic cells (DC) isolated from nontreated mice showed low surface expression of MHC, CD1d, and CD40, CD80, or CD86 costimulator molecules that were strikingly up-regulated after αGalCer injection. Although liver CD11c+ DC displayed lower CD1d surface expression than hepatocytes, they were potent stimulators of IFN-γ and IL-4 release by liver NKT when pulsed with αGalCer in vitro or in vivo. Liver DC are thus potent stimulators of proinflammatory cytokine release by NKT cells, are activated themselves in the process of NKT cell activation, and express an activated phenotype after the NKT cell population is eliminated following αGalCer stimulation.

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Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice

et al. 2004

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Inhibition of concanavalin A-induced hepatic injury of mice by bacterial lipopolysaccharide via the induction of IL-6 and the subsequent reduction of IL-4: the cytokine milieu of concanavalin A hepatitis

Cited by 27 publications

References 31 publications

C-C Chemokine Ligand 2/Monocyte Chemoattractant Protein-1 Directly Inhibits NKT Cell IL-4 Production and Is Hepatoprotective in T Cell-Mediated Hepatitis in the Mouse

C-C Chemokine Ligand 2/Monocyte Chemoattractant Protein-1 Directly Inhibits NKT Cell IL-4 Production and Is Hepatoprotective in T Cell-Mediated Hepatitis in the Mouse

Activating Immunity in the Liver. I. Liver Dendritic Cells (but Not Hepatocytes) Are Potent Activators of IFN-γ Release by Liver NKT Cells

Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice

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