The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition

Garbers, Christoph; Aparicio-Siegmund, Samadhi; Rose-John, Stefan

doi:10.1016/j.coi.2015.02.008

Cited by 357 publications

(293 citation statements)

References 62 publications

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“…Inhibition of trans-signaling has been shown to be sufficient to block disease progression, leading to the conclusion that the trans-signaling branch of IL-6 signaling is mainly responsible for the detrimental chronic pro-inflammatory activities of IL-6 (5, 9). These conclusions stem from the observation that sgp130Fc, which is an Fc-dimerized version of sgp130, specifically blocks IL-6 trans-signaling and is highly efficacious in diverse models of chronic inflammation (3,5,7). Interestingly, dimerization increased the efficacy to block signaling via IL-6/sIL-6R by a factor of 10 -100 compared with monomeric sgp130 (7), which might be explained by the homodimeric nature of gp130 in the IL-6 signaling complex.…”

Section: Discussionmentioning

confidence: 99%

“…When seen in combination with sIL-6R, they could likely represent a buffer system to prevent that local peaks of IL-6 have systemic effects. In this context, IL-6 binds to sIL-6R with 1 mM affinity, and this IL-6⅐sIL-6R complex binds to sgp130 with 10 pM affinity and is immediately neutralized rather than being able to activate a target cell because the IL-6⅐sIL-6R⅐sgp130 complexes form quickly and are biologically inactive (3,5,30). The capacity of this buffer is controlled by the amount of sIL-6R, as sgp130 is present in molar excess over sIL-6R (5).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…In addition to effects on the gut barrier, IL-22 has also been shown to be hepatoprotective in models of acute liver injury (13) and in models of alcohol-induced hepatitis (14,15). Other than IL-22 receptor signaling, activation of the IL-6 signal transducer glycoprotein 130 (gp130) through IL-6R can also initiate Jak/STAT signaling in the liver (16).…”

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confidence: 99%

Therapeutic Role of Interleukin 22 in Experimental Intra-abdominal Klebsiella pneumoniae Infection in Mice

et al. 2016

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Hep؊/؊ ) and Stat3 knockout (Stat3 Hep؊/؊ ) mice were generated and subjected to intra-abdominal infection with Klebsiella pneumoniae, which results in liver injury and necrosis. We found that overexpression of IL-22 or therapeutic administration of recombinant IL-22 (rIL-22), given 2 h postinfection, significantly reduced the bacterial burden in both the liver and spleen. The antimicrobial activity of rIL-22 required hepatic Il22Ra1 and Stat3. Serum from rIL-22-treated mice showed potent bacteriostatic activity against K. pneumoniae, which was dependent on lipocalin 2 (LCN2). However, in vivo, rIL-22-induced antimicrobial activity was only partially reduced in LCN2-deficient mice. We found that rIL-22 also induced serum amyloid A2 (SAA2) and that SAA2 had anti-K. pneumoniae bactericidal activity in vitro. These results demonstrate that IL-22, through IL-22Ra1 and STAT3 singling, can induce intrinsic antimicrobial activity in the liver, which is due in part to LCN2 and SAA2. Therefore, IL-22 may be a useful adjunct in treating hepatic and intra-abdominal infections.

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“…This characteristic indicates the probable contribution of regulatory B cells in association with immune system responses in healthy people and patients. In T cells, the IL-35 signals encompass three receptor subunits comprising IL-12R-β2-IL-12R-β2, IL-12R-β2-gp130, and gp130-gp130 which activate STAT1 and STAT4 molecules [23,28,75,140,141].…”

Section: Il-35 Receptors and Signalling Pathwaymentioning

confidence: 99%

IL-12 Family Cytokines: General Characteristics, Pathogenic Microorganisms, Receptors, and Signalling Pathways

Behzadi¹,

Behzadi²,

Ranjbar³

2016

Acta Microbiologica et Immunologica Hungarica

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Among a wide range of cytokines, the Interleukin 12 (IL-12) family has its unique structural, functional, and immunological characteristics that have made this family as important immunological playmakers. Because of the importance of IL-12 heterodimeric cytokines in microbial infections, autoimmune diseases, and cancers, the authors of this literature discuss about the general characteristics of IL-12 family members, the interactions between IL-12 cytokines and pathogenic microorganisms, the interleukins receptors and their strategies for selecting different signalling pathways. IL-12 and IL-23 are similar in p40 subunits and both are involved in proinfl ammatory responses while, IL-27 and IL-35 contribute to anti-infl ammatory activities; however, IL-27 is also involved in pro-infl ammatory responses. There are some similarities and dissimilarities among IL-12 family members which make them a unique bridge between innate and adaptive immune systems. The bioactivities of IL-12 family indicate a brilliant promise for their applications in different fi elds of medicine. The members of IL-12 family are candidate for several therapeutics including gene therapy, cancer therapy, tumour therapy, and vaccination. To have an accurate diagnostic technique and defi nite treatment regarding to infectious diseases, the playmakers of IL-12 family as effective criteria together with microarray technology are the best choices for current and future applications.

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The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition

Cited by 357 publications

References 62 publications

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

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

Therapeutic Role of Interleukin 22 in Experimental Intra-abdominal Klebsiella pneumoniae Infection in Mice

IL-12 Family Cytokines: General Characteristics, Pathogenic Microorganisms, Receptors, and Signalling Pathways

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