Involvement of IL-10, an anti-inflammatory cytokine in murine liver injury induced by Concanavalin A

Kato, Mitsuro; Ikeda, Naoki; Matsushita, Eiki; Kaneko, Shuichi; Kobayashi, Kenichi

doi:10.1016/s1386-6346(00)00137-6

Cited by 40 publications

(24 citation statements)

References 34 publications

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“…In addition, Villarino et al (25) reported hyperactivation of WSX-1-deficient CD4 ϩ T cells during T. gondii infection. Although the precise molecular mechanisms for the overproduction of cytokines and cellular activation are under investigation, the involvement of IL-10, an antiinflammatory cytokine (18), is unlikely, because the production of IL-10 was not reduced in WSX-1-deficient mice compared with that in wild-type mice after Con A treatment (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Hyperproduction of Proinflammatory Cytokines by WSX-1-Deficient NKT Cells in Concanavalin A-Induced Hepatitis

Yamanaka

Hamano

Miyazaki

et al. 2004

The Journal of Immunology

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Administration of Con A induces liver injury that is considered to be an experimental model for human autoimmune or viral hepatitis, where immunopathology plays roles mediated by activated lymphocytes, especially NK1.1+ CD3+ NKT cells, and inflammatory cytokines, including IFN-γ and IL-4. In the present study we investigated the role of WSX-1, a component of IL-27R, in Con A-induced hepatitis by taking advantage of WSX-1 knockout mice. WSX-1-deficient mice were more susceptible to Con A treatment than wild-type mice, showing serum alanine aminotransferase elevation and massive necrosis in the liver. Although the development of NKT cells appeared normal in WSX-1 knockout mice, purified NKT cells from the knockout mice produced more IFN-γ and IL-4 than those from wild-type mice in response to stimulation with Con A both in vitro and in vivo. In addition, hyperproduction of proinflammatory cytokines, including IL-1, IL-6, and TNF-α, was observed in the knockout mice after Con A administration. These data revealed a novel role for WSX-1 as an inhibitory regulator of cytokine production and inflammation in Con A-induced hepatitis.

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Section: Discussionmentioning

confidence: 99%

Hyperproduction of Proinflammatory Cytokines by WSX-1-Deficient NKT Cells in Concanavalin A-Induced Hepatitis

Yamanaka

Hamano

Miyazaki

et al. 2004

The Journal of Immunology

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“…The mechanisms balancing the levels and time courses of pro-versus anti-inflammatory mediators in tissue macrophages are only beginning to be understood and can best be worked out through comparative studies of various combinations of cytokines produced from the same cell source in the infected tissue. Kupffer cells are important producers of TNF-␣, IL-10, and IL-6 in vivo, and the balance in the levels of these cytokines is not only essential for immune responses locally in the liver but may also alter systemic levels of pro-and anti-inflammatory cytokines (11,13,25,43,56). IL-10 has the ability to suppress proinflammatory cytokine release and may protect against the onset of irreversible sepsis (28), and hence, the initial local TNF-␣-IL-10 balance is crucial for further development of the inflammatory process.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, Kupffer cells have been demonstrated to be major producers of circulating interleukin-6 (IL-6) during trauma (43). Moreover, production of the anti-inflammatory cytokine IL-10 by Kupffer cells was recently shown to be essential for protection against peritonitis (13), and IL-10 production and signaling have been proven to be important for protection against liver injury in mice (11,25). It was also recently reported that an early rise in IL-6 and IL-10 occurred in plasma during liver surgery, whereas the level of the proinflammatory cytokine TNF-␣ remained low (21).…”

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confidence: 99%

The Phosphatidylinositol 3-Kinase/Protein Kinase B Signaling Pathway Is Activated by Lipoteichoic Acid and Plays a Role in Kupffer Cell Production of Interleukin-6 (IL-6) and IL-10

Dahle¹,

Øverland²,

Myhre³

et al. 2004

Infect Immun

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Sepsis caused by gram-positive bacteria lacking lipopolysaccharide (LPS) has become a major and increasing cause of mortality in intensive-care units. We have recently demonstrated that the gram-positive-specific bacterial cell wall component lipoteichoic acid (LTA) stimulates the release of the proinflammatory cytokines in Kupffer cells in culture. In the present study, we have started to assess the signal transduction events by which LTA induces the production of tumor necrosis factor alpha (TNF-␣), interleukin-6 (IL-6), and the anti-inflammatory cytokine IL-10 in rat Kupffer cells. LTA was found to trigger phosphorylation of mitogenactivated protein kinases (MAPK) (p38 MAPK and ERK 1/2) and protein kinase B (PKB). Compared to LPS, LTA was more potent in inducing PKB phosphorylation after 40 min, although we found that the cytokine responses were similar. For both bacterial molecules, blocking phosphatidylinositol 3-kinase (PI3-K; Ly294002) or Janus kinase 2 (JAK-2; AG490) particularly affected the induction of IL-6 and IL-10 release, whereas TNF-␣ levels were strongly reduced by inhibition of Src family tyrosine kinases (PP2). All three cytokines were reduced by inhibition of p38 MAPK (SB202190) or the broad-range tyrosine kinase inhibitor genistein, whereas IL-6 release was particularly blocked by inhibition of ERK 1/2 (PD98059). Divergences in the regulatory pathways controlling TNF-␣, IL-10, and IL-6 production in Kupffer cells following LPS or LTA stimulation may create a basis for understanding how the balance between pro-and anti-inflammatory cytokines is regulated in the liver following infections by gram-positive or gram-negative bacteria.

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“…Recently, it has been shown that propagermanium, an anti-inflammatory drug used clinically for the treatment of chronic hepatitis, prevented Con A-induced liver injury through interference with monocyte/macrophage recruitment mediated by MCP-1 (Yokochi et al, 2001). Several studies show that cytokines such as IL-6, IL-10, and TGF-␤ are also up-regulated during the onset of hepatitis and play a role in reducing liver inflammation (Mizuhara et al, 1994;Kato et al, 2001). In the spleen, PRS-211,092 augmented IL-10 gene expression by 150% at 15 min and 1 h after Con A challenge (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Among the pro-inflammatory cytokines, tumor necrosis factor ␣ (TNF␣) and interferon ␥ play a major role in Con A-induced liver cell damage (Mizuhara et al, 1994;Gantner et al, 1995;Kusters et al, 1996;Mizuhara et al, 1996). These cytokines are negatively regulated by interleukin (IL)-10, whereas IL-6 plays a bimodal role in liver inflammation (Louis et al, 1997;Tagawa et al, 2000;Kato et al, 2001). Recent studies have shown that IL-10 and IL-6 counteract inflammation by a mechanism that involves the induction of the suppressor of cytokines signaling (SOCS) family of proteins.…”

mentioning

confidence: 99%

A Novel Synthetic Cannabinoid Derivative Inhibits Inflammatory Liver Damage via Negative Cytokine Regulation

Lavon¹,

Sheinin²,

Meilin³

et al. 2003

Molecular Pharmacology

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The therapeutic potential of cannabinoids has been described previously for several inflammatory diseases, but the molecular mechanisms underlying the anti-inflammatory properties of cannabinoids are not well understood. In this study, we investigated the mechanism of action of a novel synthetic cannabinoid, [(ϩ)-(6aS,10aS)-6,6-Dimethyl-3-(1,1-dimethylheptyl)-1-hydroxy-9-(1H-imidazol-2-ylsulfanylmethyl]-6a,7,10,10a-tetrahydro-6H-dibenzo [b,d]pyran 092) that has no psychotropic effects but exhibits immunomodulatory properties. Treatment with PRS-211,092 significantly decreased Concanavalin A-induced liver injury in mice that was accompanied by: 1) promotion of early gene expression of interleukin (IL)-6 and IL-10 that play a protective role in this model; 2) induction of early gene expression of the suppressors of cytokine signaling (SOCS-1 and 3), followed by 3) inhibition of several pro-inflammatory mediators, including IL-2, monocyte chemoattractant protein-1 (MCP-1), IL-1␤, interferon-␥, and tumor necrosis factor ␣. Based on these results, we propose a mechanism by which PRS-211,092 stimulates the expression of IL-6, IL-10 and the SOCS proteins that, in turn, negatively regulates the expression of pro-inflammatory cytokines. Negative regulation by PRS-211,092 was further demonstrated in cultured T cells, where it inhibited IL-2 production and nuclear factor of activated T cells activity. These findings suggest that this cannabinoid derivative is an immunomodulator that could be developed as a potential drug for hepatitis as well as for other short-or long-term inflammatory diseases.The identification of ⌬ 9 -tetrahydrocannabinol as the active component of marijuana (Cannabis sativa) prompted medicinal chemists to develop numerous cannabinoid analogs and opened a new era in research on the pharmaceutical applications of these compounds. Mechoulam (2000) discovered that the undesirable psychotropic effects of cannabinoids lie in a specific configuration of the molecule. This situation was best exemplified with the HU-210 and HU-211 enantiomeric pair of synthetic cannabinoids, HU-210 has the natural configuration and is 100 times more psychoactive than ⌬ 9

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Involvement of IL-10, an anti-inflammatory cytokine in murine liver injury induced by Concanavalin A

Cited by 40 publications

References 34 publications

Hyperproduction of Proinflammatory Cytokines by WSX-1-Deficient NKT Cells in Concanavalin A-Induced Hepatitis

Hyperproduction of Proinflammatory Cytokines by WSX-1-Deficient NKT Cells in Concanavalin A-Induced Hepatitis

The Phosphatidylinositol 3-Kinase/Protein Kinase B Signaling Pathway Is Activated by Lipoteichoic Acid and Plays a Role in Kupffer Cell Production of Interleukin-6 (IL-6) and IL-10

A Novel Synthetic Cannabinoid Derivative Inhibits Inflammatory Liver Damage via Negative Cytokine Regulation

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