Inhibition of Classic Signaling Is a Novel Function of Soluble Glycoprotein 130 (sgp130), Which Is Controlled by the Ratio of Interleukin 6 and Soluble Interleukin 6 Receptor

Garbers, Christoph; Thaiss, Wolfgang M.; Jones, Gareth Wyn; Waetzig, Georg H.; Lorenzen, Inken; Guilhot, Joëlle; Lissilaa, Rami; Ferlin, Walter; Grötzinger, Joachim; Jones, Simon A.; Rose-John, Stefan; Scheller, Jürgen

doi:10.1074/jbc.m111.295758

Cited by 142 publications

(148 citation statements)

References 45 publications

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“…A similar reduction of mIL-6Ra expression was also observed in infected IL-6 KO mice, which excludes IL-6-induced receptor internalization or interference of IL-6 with anti-IL6Ra mAb binding to IL-6Ra as a cause for low IL-6Ra surface staining (50). Shedding of mIL-6Ra by ADAM10 and ADAM17 has been identified as a general mechanism of sIL-6Ra generation in mice (51), and it is very likely that shedding is responsible for the loss of IL-6Ra surface expression following L. monocytogenes infection. TCR triggering has been described as a signal for IL6Ra shedding (52,53); however, the global loss of IL-6Ra on naive and effector cells argues against a specific TCR signal at this early stage of infection.…”

Section: Discussionmentioning

confidence: 54%

IL-6 Controls the Innate Immune Response against Listeria monocytogenes via Classical IL-6 Signaling

Hoge

Yan

Jänner

et al. 2013

The Journal of Immunology

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132

107

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The cytokine IL-6 plays a protective role in immune responses against bacterial infections. However, the mechanisms of IL-6–mediated protection are only partially understood. IL-6 can signal via the IL-6R complex composed of membrane-bound IL-6Rα (mIL-6Rα) and gp130. Owing to the restricted expression of mIL-6Rα, classical IL-6 signaling occurs only in a limited number of cells such as hepatocytes and certain leukocyte subsets. IL-6 also interacts with soluble IL-6Rα proteins and these IL-6/soluble IL-6Rα complexes can subsequently bind to membrane-bound gp130 proteins and induce signaling. Because gp130 is ubiquitously expressed, this IL-6 trans-signaling substantially increases the spectrum of cells responding to IL-6. In this study, we analyze the role of classical IL-6 signaling and IL-6 trans-signaling in the innate immune response of mice against Listeria monocytogenes infection. We demonstrate that L. monocytogenes infection causes profound systemic IL-6 production and rapid loss of IL-6Rα surface expression on neutrophils, inflammatory monocytes, and different lymphocyte subsets. IL-6–deficient mice or mice treated with neutralizing anti–IL-6 mAb displayed impaired control of L. monocytogenes infection accompanied by alterations in the expression of inflammatory cytokines and chemokines, as well as in the recruitment of inflammatory cells. In contrast, restricted blockade of IL-6 trans-signaling by application or transgenic expression of a soluble gp130 protein did not restrain the control of infection. In summary, our results demonstrate that IL-6Rα surface expression is highly dynamic during the innate response against L. monocytogenes and that the protective IL-6 function is dependent on classical IL-6 signaling via mIL-6Rα.

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Section: Discussionmentioning

confidence: 54%

IL-6 Controls the Innate Immune Response against Listeria monocytogenes via Classical IL-6 Signaling

Hoge

Yan

Jänner

et al. 2013

The Journal of Immunology

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132

107

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“…Cells-It is well established that exogenous addition of recombinant sgp130 or sgp130Fc is able to block proliferation of Ba/F3-gp130 that is induced by IL-6 trans-signaling (7,8). However, our data with primary monocytes show that cells can secrete sgp130, possibly to protect themselves against trans-signaling.…”

Section: Cell-autonomous Secretion Of Sgp130 Is Sufficient To Block Pmentioning

confidence: 60%

“…Classic signaling can only be influenced by sgp130 under certain conditions when sIL-6R is present in molar excess over IL-6 (8). However, correct dosing of sgp130Fc ensures exclusive blockade of IL-6 trans-signaling (8).…”

Section: Discussionmentioning

confidence: 99%

“…Soluble forms of gp130 (sgp130) exist in human serum at concentrations of up to 400 ng/ml (6) and have been shown to act as natural inhibitors of IL-6 trans-signaling (7), although, at high concentrations, they can interfere with classic signaling as well (8). Interestingly, specific inhibition of trans-signaling with an Fc-dimerized version of sgp130 (sgp130Fc) has been shown to be beneficial in numerous inflammatory diseases and cancer (9,10).…”

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confidence: 99%

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Different Soluble Forms of the Interleukin-6 Family Signal Transducer gp130 Fine-tune the Blockade of Interleukin-6 Trans-signaling

Wolf

Waetzig

Chalaris

et al. 2016

Journal of Biological Chemistry

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Soluble forms of the IL-6 receptor (sIL-6R) bind to the cytokine IL-6 with similar affinity as the membrane-bound IL-6R. IL-6⅐sIL-6R complexes initiate IL-6 trans-signaling via activation of the ubiquitously expressed membrane-bound ␤-receptor glycoprotein 130 (gp130). Inhibition of IL-6 trans-signaling has been shown to be favorable in numerous inflammatory diseases. Furthermore, different soluble forms of gp130 (sgp130) exist that, together with the sIL-6R, are thought to form a buffer for IL-6 in the blood. However, a functional role for the different sgp130 forms has not been described to date. Here we demonstrate that the metalloproteases ADAM10 and ADAM17 can produce sgp130 by ectodomain shedding of gp130, even though this mechanism only accounts for a minor proportion of sgp130 in the circulation. We further show that full-length sgp130 and the shorter forms sgp130-rheumatoid arthritis-associated peptide (RAPS) and sgp130-E10 are differentially expressed in a cell type-specific manner. Remarkably, full-length sgp130 is expressed by monocytes, but this expression is completely lost during differentiation into macrophages in vitro. Using genetically engineered murine pre-B cells that secrete different forms of sgp130, we found that these secreted sgp130 proteins are able to prevent trans-signaling-driven cell proliferation of the secreting cells, whereas conditioned supernatant from these cells failed to block IL-6 trans-signaling in other cells. Thus, our data suggest that the different sgp130 forms are released from cells into their immediate surroundings and appear to form cell-associated gradients to modulate their own susceptibility for IL-6 trans-signaling.IL-6 is a pleiotropic cytokine with pro-and anti-inflammatory functions (1-4). Classic signaling via the membranebound IL-6R 3 accounts for the regenerative properties of IL-6; trans-signaling via sIL-6R is rather pro-inflammatory (2, 4). In both cases, IL-6 binds initially to the (s)IL-6R, and the IL-6⅐(s)IL-6R complex recruits two signal-transducing gp130 ␤-receptors. This final IL-6⅐(s)IL-6R/gp130 complex formation initiates the activation of intracellular signaling pathways, among them Jak/STAT, PI3K, MAPK, and Src/Yes-associated protein (YAP) (5).Soluble forms of gp130 (sgp130) exist in human serum at concentrations of up to 400 ng/ml (6) and have been shown to act as natural inhibitors of IL-6 trans-signaling (7), although, at high concentrations, they can interfere with classic signaling as well (8). Interestingly, specific inhibition of trans-signaling with an Fc-dimerized version of sgp130 (sgp130Fc) has been shown to be beneficial in numerous inflammatory diseases and cancer (9, 10). sgp130Fc is currently in clinical development as a drug candidate to treat inflammatory bowel diseases (11).gp130 is a transmembrane protein with three N-terminal Iglike domains followed by three fibronectin-type III domains. sgp130 forms with molecular weights of 50, 90, and 110 kDa have been detected in human body fluids (6, 12, 13). Where and how these thre...

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“…Normal concentrations of sIL-6R are about 30-50 ng ml −1 (Garbers et al, 2012). This number can increase up to 3-fold during inflammation (Garbers et al, 2011), which increases the potential to trans-signal. In addition to the sIL-6R that allows trans-signaling, there is also a soluble form of gp130 (sgp130).…”

Section: Il-6 Cytokine Family Signalingmentioning

confidence: 99%

The role of gp130 receptor cytokines in the regulation of metabolic homeostasis

Cron

Allen

Febbraio

2016

Journal of Experimental Biology

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It is well known that obesity is responsible, at least in part, for the increased incidence of chronic diseases such as type 2 diabetes, cardiovascular disease and certain types of cancer. Despite public education programs emphasizing lifestyle modifications to arrest this global pandemic, it is now estimated that 10-15% of the world's population are overweight or obese. As a result, new therapeutic options for the treatment of obesity-related disorders are clearly warranted. Much of the benefit of physical activity has been attributed to several mechanisms including reduced adiposity, increased cardiorespiratory fitness, reduced circulating lipids and the maintenance of muscle mass. However, the observation that the gp130 receptor cytokine interleukin-6 (IL-6) was released from skeletal muscle during exercise to improve metabolic homeostasis altered our understanding of the health benefits of exercise and opened avenues for research into potential novel therapeutics to treat metabolic disease. One gp130 receptor cytokine in particular, ciliary neurotrophic factor (CNTF), a pluripotent neurocytokine, showed efficacy as a potential anti-obesogenic therapy. This review examines the potential of gp130 receptor ligands, with a focus on IL-6 and CNTF as therapeutic strategies to treat obesity-related disorders.

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Inhibition of Classic Signaling Is a Novel Function of Soluble Glycoprotein 130 (sgp130), Which Is Controlled by the Ratio of Interleukin 6 and Soluble Interleukin 6 Receptor

Cited by 142 publications

References 45 publications

IL-6 Controls the Innate Immune Response against Listeria monocytogenes via Classical IL-6 Signaling

IL-6 Controls the Innate Immune Response against Listeria monocytogenes via Classical IL-6 Signaling

Different Soluble Forms of the Interleukin-6 Family Signal Transducer gp130 Fine-tune the Blockade of Interleukin-6 Trans-signaling

The role of gp130 receptor cytokines in the regulation of metabolic homeostasis

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