Caspase-mediated cleavage of the signal-transducing IL-6 receptor subunit gp130

Graf, Dirk; Haselow, Katrin; Münks, Ivo; Bode, Johannes G.; Häussinger, Dieter

doi:10.1016/j.abb.2008.06.009

Cited by 12 publications

(5 citation statements)

References 55 publications

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“…Our results indicate that AR‐42 exerts an important inhibitory effect on the IL‐6 signal transduction pathway by downregulating the expression of gp130 and inhibiting constitutive and inducible STAT3 phosphorylation. While the mechanism by which gp130 is down regulated remains uncertain, the relatively late time course at which this effect is observed (24 hr) likely indicates that this occurs at the transcription level rather than degradation of the receptor subunit 47, 48. Furthermore, inhibition of STAT3 phosphorylation may further contribute to this effect on gp130 as previously reported 47.…”

Section: Discussionmentioning

confidence: 64%

The novel histone deacetylase inhibitor, AR‐42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells

Zhang

Suvannasankha

Crean

et al. 2010

Intl Journal of Cancer

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Multiple myeloma (MM) remains incurable with current therapy, indicating the need for continued development of novel therapeutic agents. We evaluated the activity of a novel phenylbutyrate-derived histone deacetylase inhibitor, AR-42, in primary human myeloma cells and cell lines. AR-42 was cytotoxic to MM cells at a mean LC50 of 0.18 ± 0.06 μmol/l at 48 hr and induced apoptosis with cleavage of caspases 8, 9 and 3, with cell death largely prevented by caspase inhibition. AR-42 downregulated the expression of gp130 and inhibited activation of STAT3, with minimal effects on the PI3K/Akt and MAPK pathways, indicating a predominant effect on the gp130/STAT-3 pathway. AR-42 also inhibited interleukin (IL)-6-induced STAT3 activation, which could not be overcome by exogenous IL-6. AR-42 also downregulated the expression of STAT3-regulated targets, including Bcl-xL and cyclin D1. Overexpression of Bcl-xL by a lentivirus construct partly protected against cell death induced by AR-42. The cyclin dependent kinase inhibitors, p16 and p21, were also significantly induced by AR-42, which together with a decrease in cyclin D1, resulted in G1 and G2 cell cycle arrest. In conclusion, AR-42 has potent cytotoxicity against MM cells mainly through gp130/STAT-3 pathway. The results provide rationale for clinical investigation of AR-42 in MM.

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Section: Discussionmentioning

confidence: 64%

The novel histone deacetylase inhibitor, AR‐42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells

Zhang

Suvannasankha

Crean

et al. 2010

Intl Journal of Cancer

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“…For example, IL-27, LIF and CNTF interaction with both their receptors and gp-130 can transiently inhibit the signaling capacity of other family members, in particular IL-6 (Zvonic et al 2005 ; Skiniotis et al 2008 ). Alternatively, the undesired effects may be explained by the degradation of the LIFR and protein gp-130 mediated by caspases and lysosomal enzymes (Zvonic et al 2005 ; Graf et al 2008 ). Finally, we do not know if IL-6 trans-signaling through the soluble IL-6R amplify IL-6 signaling in skeletal muscle of the cachectic patient.…”

Section: Final Remarksmentioning

confidence: 99%

Skeletal muscle wasting and renewal: a pivotal role of myokine IL-6

et al. 2016

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Adult skeletal tissue is composed of heterogeneous population of cells that constantly self-renew by means of a controlled process of activation and proliferation of tissue-resident stem cells named satellite cells. Many growth factors, cytokines and myokines produced by skeletal muscle cells play critical roles in local regulation of the inflammatory process and skeletal muscle regeneration during different pathological conditions. IL-6 is a pleiotropic cytokine released in large amount during infection, autoimmunity and cancer. Low levels of IL-6 can promote activation of satellite cells and myotube regeneration while chronically elevated production promote skeletal muscle wasting. These distinct effects may be explained by a crosstalk of the IL-6/IL-6 receptor and gp130 trans-signaling pathway that oppose to regenerative and anti-inflammatory of the classical IL-6 receptor signaling pathway. Here we discuss on potential therapeutic strategies using monoclonal antibodies to IL-6R for the treatment of skeletal muscle wasting and cachexia. We also highlight on the IL-6/JAK/STAT and FGF/p38αβ MAPK signaling pathways in satellite cell activation and the use of protein kinase inhibitors for tailoring and optimizing satellite cell proliferation during the skeletal muscle renewal. Future investigations on the roles of the IL-6 classical and trans-signaling pathways in both immune and non-immune cells in skeletal muscle tissue will provide new basis for therapeutic approaches to reverse atrophy and degeneration of skeletal muscles in cancer and inflammatory diseases.

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“…Specificity of RT-PCR has been controlled by no template and no RT controls. Semiquantitative PCR results were obtained as described previously [14]. Threshold values were normalized to HPRT1 and set in reference to unstimulated control cells.…”

Section: Real-time Pcrmentioning

confidence: 99%

“…Thereby, bile acids have been shown to affect the function of cytokine-driven effector mechanisms of innate immunity, as well as the function of cells of innate and adaptive immunity, including monocytes, macrophages, NK cells, and T cells. Hence, bile acids affect intracellular signaling in response to type I IFNs or cytokines, such as IL-6, and subsequent gene expression in immune cells, such as NK cells or lymphocytes, as well as in epithelial cells, such as hepatocytes [11][12][13][14][15]. Moreover, bile acids alter the primary humoral response in human monocytes by inhibition of cell proliferation and exocytosis of Ig [16], and a variety of different reports indicates that they substantially impair macrophage functions, including phagocytic activity, as well as production of the cytokines TNF-␣ or IL-6, in response to inflammatory stimuli, such as LPS [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Bile acids PKA-dependently induce a switch of the IL-10/IL-12 ratio and reduce proinflammatory capability of human macrophages

Haselow

Bode

Wammers

et al. 2013

Journal of Leukocyte Biology

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125

109

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That cholestatic conditions are accompanied by an enhanced susceptibility to bacterial infection in human and animal models is a known phenomenon. This correlates with the observation that bile acids have suppressive effects on cells of innate and adaptive immunity. The present study provides evidence that in human macrophages, bile acids inhibit the LPS-induced expression of proinflammatory cytokines without affecting the expression of the anti-inflammatory cytokine IL-10. This results in a macrophage phenotype that is characterized by an increased IL-10/IL-12 ratio. Correspondingly, bile acids suppress basal phagocytic activity of human macrophages. These effects of bile acids can be mimicked by cAMP, which is presumably induced TGR5-dependently. The data provided further suggest that in primary human macrophages, modulation of the macrophage response toward LPS by bile acids involves activation of CREB, disturbed nuclear translocation of NF-κB, and PKA-dependent enhancement of LPS-induced cFos expression. The increase in cFos expression is paralleled by an enhanced formation of a protein complex comprising cFos and the p65 subunit of NF-κB. In summary, the data provided suggest that in human macrophages, bile acids induce an anti-inflammatory phenotype characterized by an increased IL-10/IL-12 ratio via activation of PKA and thereby, prevent their activation as classically activated macrophages. This bile acid-induced modulation of macrophage function may also be responsible for the experimentally and clinically observed anti-inflammatory and immunosuppressive effects of bile acids.

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Caspase-mediated cleavage of the signal-transducing IL-6 receptor subunit gp130

Cited by 12 publications

References 55 publications

The novel histone deacetylase inhibitor, AR‐42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells

The novel histone deacetylase inhibitor, AR‐42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells

Skeletal muscle wasting and renewal: a pivotal role of myokine IL-6

Bile acids PKA-dependently induce a switch of the IL-10/IL-12 ratio and reduce proinflammatory capability of human macrophages

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