Interleukin-15 prevents concanavalin A-induced liver injury in mice via NKT cell-dependent mechanism

Li, Bofeng; Sun, Rui; Wei, Haiming; Gao, Bin; Tian, Zhigang

doi:10.1002/hep.21174

Cited by 53 publications

(49 citation statements)

References 37 publications

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“…61,62 In a model of IL-4-induced rat hepatitis, IL-4 serum concentrations reached 1800 pg/ml. 63 In HIV-Trypanosoma cruzi coinfection, IL-4 serum levels reached 6200 pg/ml. 64 Intrahepatic concentrations were unknown.…”

Section: Discussionmentioning

confidence: 98%

Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway

Aoudjehane

Pissaia

Scatton

et al. 2008

Laboratory Investigation

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Interleukin-4 (IL-4) is overexpressed in liver grafts in a context of severe recurrent hepatitis C, during which the development of fibrosis is dramatically accelerated. In this study, we examined the effects of IL-4 on the activation and collagen production of cultured human intrahepatic (myo)fibroblasts (hIHFs), and investigated the underlying mechanisms. The myofibroblastic nature of cells was evaluated morphologically using activation markers (smooth muscle a-actin, vimentin and prolyl 4-hydroxylase). Quiescent hIHFs were obtained by cell incubation in serum-free medium or cell culture on Matrigel. We first analyzed IL-4 receptor expression, STAT-6 activation by IL-4, and STAT-6 inhibition by an anti-IL-4 antibody or by STAT-6 small-interfering RNA (siRNA) transfection. We then focused on collagen production, using quantitative real-time PCR to analyze the effect of IL-4 on the mRNA expression of collagens I, III and IV, and on collagen levels in supernatants of hIHFs, using the Sircol collagen assay. hIHFs cultured in plastic wells appeared to be morphologically activated. The expression of activation markers was reduced by serum deprivation or culture on Matrigel, and restored by IL-4 incubation. The IL-4 receptor was expressed by hIHFs, and STAT-6 was activated following incubation with IL-4. Both anti-IL-4 antibody and STAT-6 siRNA transfection inhibited this activation. The treatment of hIHFs with IL-4 increased the mRNA expression of collagens I, III and IV (Po0.05) and elevated collagen levels in supernatants (P ¼ 0.01 vs untreated cells). Therefore, IL-4 exerts profibrotic effects by activating hIHFs and inducing collagen production and secretion. This effect requires IL4-R binding and STAT-6 activation. IL-4 may thus be involved in accelerated course of fibrogenesis during recurrent hepatitis C.

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Section: Discussionmentioning

confidence: 98%

Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway

Aoudjehane

Pissaia

Scatton

et al. 2008

Laboratory Investigation

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“…Other experiments have shown that effector CD8 ϩ T cells can transiently modulate hepatocytes, which in turn activate naive CD8 ϩ T cells of unrelated specificities, enhance NKT cell activation, and induce the synthesis of cytokines that can promote both innate and adaptive immune responses (76). Thus, communication with innate immunity may help to spread a "defense" alarm and also provide a further mechanism to dampen hepatic injury by activated CD8 ϩ T cells (77,78).…”

Section: Discussionmentioning

confidence: 99%

Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill

Keating

Yue

Rutigliano

et al. 2007

The Journal of Immunology

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Influenza A virus infection of C57BL/6 mice is a well-characterized model for studying CD8+ T cell-mediated immunity. Analysis of primary and secondary responses showed that the liver is highly enriched for CD8+ T cells specific for the immunodominant H2DbNP366–374 (DbNP366) epitope. Functional analysis established that these liver-derived virus-specific CD8+ T cells are fully competent cytotoxic effectors and IFN-γ secretors. In addition, flow cytometric analysis of early apoptotic cells showed that these influenza-specific CD8+ T cells from liver are as viable as those in the spleen, bronchoalveolar lavage, mediastinal lymph nodes, or lung. Moreover, cytokine profiles of the influenza-specific CD8+ T cells recovered from different sites were consistent with the bronchoalveolar lavage, rather than liver population, being the most susceptible to activation-induced cell death. Importantly, adoptively transferred influenza virus-specific CD8+ T cells from the liver survived and were readily recalled after virus challenge. Together, these results show clearly that the liver is not a “graveyard” for influenza virus-specific CD8+ T cells.

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“…32 Indeed, NKT cell production of IL-5 led to the recruitment of eosinophils to the liver following ConA administration and strongly promoted hepatocellular injury, a process that could be prevented by IL15. 33 Kanzaki et al 34 reported the presence of functionally active TGF␤-Smad3 signaling in human eosinophils. Inhibition of Smad3 activation led to decreased viability of eosinophils in culture.…”

Section: Discussionmentioning

confidence: 99%

Pivotal role of Smad3 in a mouse model of T cell-mediated hepatitis

et al. 2007

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Transforming growth factor beta (TGF␤) promotes hepatocellular apoptosis and suppresses hepatic lymphocyte responses in part through activation of Smad3. The purpose of the current study was to determine the importance of Smad3 signaling in an experimental model of autoimmune hepatitis induced by concanavalin A (ConA), a process involving T cell activation and hepatocellular apoptosis. C57Bl/6 wild-type (Wt) or Smad3-deficient (Smad3 ؊/؊ ) mice were injected intravenously with 15 mg/kg ConA or vehicle. Nine hours post ConA injection, Wt mice presented with severe hepatitis as assessed by increased liver transferases. This injury was associated with eosinophil accumulation and preceded at 3 hours post-injection by significant increases in hepatic T helper 1 (interferon gamma) and T helper 2 (interleukin-4) cytokine production. Absence of Smad3 significantly blunted hepatocellular injury 9 hours post ConA injection, which was associated with reduced early T helper 1 and T helper 2 cytokine production and eosinophil accumulation. Smad3 ؊/؊ livers also showed significant reductions in hepatocellular apoptosis as assessed by terminal UTP nick-end labeling when compared to ConA-treated Wt mice in conjunction with reduced caspase 3 cleavage, which was likely mediated by a Smad3-dependent inhibition of the survival factor extracellular signal-regulated kinase 1/2. In vitro, Smad3 ؊/؊ hepatocytes were resistant to TGF␤-induced apoptosis, and this protection was dependent on extracellular signal-regulated kinase activation. Conclusion: Together, these results show, for the first time, the significance of Smad3 signaling in autoimmune hepatitis, underlining the control of Smad3-dependent TGF␤ signaling on proinflammatory cytokine production, eosinophil recruitment, and hepatocellular apoptosis. Interruption of this pathway could be beneficial clinically to limit acute fulminant liver pathologies. ( The inherent ability of TGF␤ to regulate immune responses is strong evidence for it being an endogenous regulator of T cell function. 2 In fact, TGF␤ exerts great impact on T cells, as is evident in mice with a T cellspecific blockade of TGF␤ signaling, which resulted in the activation of a self-targeted immune response. 3,4 Additionally, recent studies in mice and humans have elucidated an important and complex role for TGF␤ in autoimmune diseases, 5 which are very often mediated by disrupted T cell signaling. 6 Inhibition of TGF␤ is associated with increased susceptibility to different experimental models of autoimmune diseases, including rheumatoid arthritis, insulin-dependent (type 1) diabetes mellitus, and inflammatory bowel disease. 7-9 Surprisingly, the role of TGF␤ in autoimmune hepatitis is not known. Recent work suggests that TGF␤ inhibits the development of immunopathology to self or otherwise nonharmful antigens without compromising immune responses to pathogens. This appears to be achieved by TGF␤-controlled initiation and resolution of inflammatory responses mediated by the regulation of chemotaxis, activation, and...

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Interleukin-15 prevents concanavalin A-induced liver injury in mice via NKT cell-dependent mechanism

Cited by 53 publications

References 37 publications

Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway

Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway

Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill

Pivotal role of Smad3 in a mouse model of T cell-mediated hepatitis

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