Soluble gp130 is the natural inhibitor of soluble interleukin‐6 receptor transsignaling responses

Jostock, Thomas; Mullberg, Jürgen; Özbek, Suat; Atreya, Raja; Blinn, Guido; Voltz, Nicole; Fischer, Martina; Neurath, Markus F.; Rose–John, Stefan

doi:10.1046/j.1432-1327.2001.01867.x

Cited by 562 publications

(592 citation statements)

References 49 publications

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“…59 A control of this form of IL-6-mediated inflammatory response may be used to induce tolerance towards genetically engineered myoblasts, and therefore it can pave the way to successful long-term gene therapy. Jostock et al 60 demonstrated that the synthetic soluble gp130Fc fusion protein (sgp130Fc) can bind to IL-6/sIL-6R complexes; consequently, a molar excess of sgp130Fc led to a competitive inhibition of the IL-6/IL-6R response, without affecting activities through the membrane-bound IL-6R. sgp130Fc has been successfully used to impair the expression of MCP-1 in a model of air pouch inflammation and to control inflammation in experimental arthritis.…”

Section: Muscle Cells Recruit Leukocytesmentioning

confidence: 99%

Skeletal muscle cells: from local inflammatory response to active immunity

et al. 2010

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The skeletal muscles are the major living component of the human body. They are constituted by stable cells, the myofibres, and by adult multipotent stem cells, the satellite cells, which can multiply to regenerate and repair the damaged tissues. Injections of DNA in muscle cells have been used to produce recombinant proteins with opposite goals: somatic reparation of genetic defects, which needs to elicit no inflammatory or immune response, and DNA vaccination, which needs a robust immune response. Because of possible therapeutical interventions, a growing body of information is being produced dealing with every aspect of the myofibres during inflammatory and autoimmune responses: skeletal muscle-antigen presenting cell (APC) interaction and intrinsic APC capabilities of myoblasts and myocytes, the response to released cytokines and their endogenous production, the regulation of Toll-like receptors and major histocompatibility complex expression. According to these data, the muscle tissue is now emerging no longer as a passive bystander, but more as an active player that, when correctly manipulated, can drive tolerance or immunization to these de novo produced proteins. In the present review, we summarize the recent developments on the control of muscle immune function.

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Section: Muscle Cells Recruit Leukocytesmentioning

confidence: 99%

Skeletal muscle cells: from local inflammatory response to active immunity

et al. 2010

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“…In turn, the IL-6Rα/IL-6 complex initiates homodimerization of gp130, an associated molecule of the IL-6 cell surface receptor. The gp130 complex is then capable of transducing the original IL-6 signal intracellularly [35]. An alternate signaling pathway for IL-6 utilizes a soluble form of the IL-6 receptor (sIL-6Rα).…”

Section: Elucidation Of An Il-6 Trans-signaling Mechanismmentioning

confidence: 99%

“…It is interesting to note that cells that do not express the membrane form of the IL-6Rα but express gp130 are rendered responsive to the IL-6/sIL-6Rα complex. This mode of action has been termed IL-6 trans-signaling [35]. Accordingly, soluble forms of gp130 are capable of competitively inhibiting IL-6 trans-signaling by binding to sIL-6Rα/IL-6 complexes, thereby eliminating their interaction with membrane-bound gp130 [35].…”

Section: Elucidation Of An Il-6 Trans-signaling Mechanismmentioning

confidence: 99%

Primary immune surveillance: some like it hot

et al. 2007

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The thermal element of fever has been found to be beneficial in models of infectious disease. The contributions of fever-range temperatures to the efficacy of the adaptive immune response have only begun to be delineated. There is accumulating evidence that fever-range thermal stress bolsters primary immune surveillance of lymph nodes and Peyer patches by augmenting lymphocyte extravasation across specialized vessels termed high endothelial venules. Molecular mechanisms have recently come to light by which the thermal component of fever alone may promote lymphocyte trafficking, and thereby the probability of mounting a defense against microbial infection. Acquired knowledge of the molecular changes associated with thermal stress may allow for the development of novel therapies for a variety of disease processes.

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“…on April 3, 2019. by guest www.bloodjournal.org From sgp130Fc is a fusion protein of the extracellular portion of gp130 and the Fc-portion of IgG1. 24 Both recombinant proteins were expressed and purified as previously described. The anti-mIL6R D7715A7 monoclonal antibody (mAB) was from BIOZOL (Eching, Germany).…”

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confidence: 99%

“…Significantly, sgp130 has previously been noted to exhibit low affinity for certain other IL6-related cytokines such as leukemia inhibitory factor (LIF). 15,24,41 However, these additional interactions appear to have limited biologic impact because sgp130Fc transgenic mice bred normally, unlike LIF-deficient female mice, which are infertile. 42 Importantly, we could also demonstrate that the sgp130Fc protein was not only found in the circulation but also in the air pouch compartment where the concentrations of the protein were high enough to achieve neutralization of IL6 transsignaling.…”

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Transgenic blockade of interleukin 6 transsignaling abrogates inflammation

Rabe

Chalaris

May

et al. 2008

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IntroductionIL6 has major functions in inflammatory reactions of the body. 1,2 Mice with a targeted inactivation of the IL6 gene are completely protected in animal models of rheumatoid arthritis 3,4 and multiple sclerosis. 5 Furthermore, regenerative reactions such as wound healing and liver regeneration are severely compromised in IL6 Ϫ/Ϫ mice. 6 A soluble form of the IL6R can bind IL6 with the same affinity as the membrane-bound form and the complex of IL6 and the soluble IL6R (sIL6R) can induce signaling in a process called IL6 transsignaling. 7,8 Because the IL6R is only sparely expressed, IL6 transsignaling dramatically increases the number of potential IL6 target cells. 9 This is relevant for inflammatory processes in vivo, because endothelial cells and smooth muscle cells, which play key roles in inflammation, lack IL6R expression. The interest in the role of IL6 in inflammatory processes has recently been intensified by the finding that the differentiation of TH 17 cells, which is a prerequisite for inflammatory damage during autoimmune disease, shows a dependence on IL6 in combination with TGF␤. 10 Recent studies with animal models of inflammatory bowel disease, 11,12 peritonitis, 13 rheumatoid arthritis, 14,15 and inflammatory colon cancer 16 suggest that IL6 transsignaling serves as the major proinflammatory paradigm of IL6 signaling under pathophysiologic conditions.To further analyze the relevance of IL6-transsignaling in vivo we generated a mouse model in which IL6-transsignaling is specifically abrogated. There have been reports describing the generation of knock-in mice with noncleavable L-selectin and noncleavable TNF-␣, showing that shedding of membrane proteins was important for antigen-stimulated lymphocyte migration and for secondary lymphoid organ architecture. 17,18 Such a strategy is impractical in the case of the sIL6R because its generation is complex and can be generated by ectodomain shedding as well as by translation from an alternatively spliced mRNA. Furthermore, shedding of the IL6R was also shown to occur at multiple cleavage sites and performed by multiple and distinct sheddase activities. [19][20][21][22] We therefore decided to generate transgenic mice overexpressing the sgp130Fc-protein that had been demonstrated to completely block IL6 transsignaling without affecting activities via the membrane bound IL6R. Blocking of IL6 transsignaling via sgp130Fc is independent of the mode of sIL6R generation. The need for a large molar excess of the sgp130Fc-protein necessitated the development of a codon optimization strategy that should be relevant for the construction of all animal models, which are based on the overexpression of heterologous proteins.The data presented here clearly show that sgp130Fc transgenic mice display an IL6-transsignaling knockout-like phenotype and establish them as the only possible in vivo model of this IL6-transsignaling paradigm. Here, we demonstrate in the air-pouch model of inflammatory activation that the transition from the neutrophil-dominated phase...

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Soluble gp130 is the natural inhibitor of soluble interleukin‐6 receptor transsignaling responses

Cited by 562 publications

References 49 publications

Skeletal muscle cells: from local inflammatory response to active immunity

Skeletal muscle cells: from local inflammatory response to active immunity

Primary immune surveillance: some like it hot

Transgenic blockade of interleukin 6 transsignaling abrogates inflammation

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