The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6.

Peters, Malte; Jacobs, Samuel A.; Ehlers, Marc; Vollmer, Petra; Mullberg, Jürgen; Wolf, Eckhard; Brem, Gottfried; Büschenfelde, K H Meyer zum; Rose-John, Stefan

doi:10.1084/jem.183.4.1399

Cited by 254 publications

(216 citation statements)

References 56 publications

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“…13 Soluble cytokine receptors such as sIL6R function to maintain the circulating half-life of their inflammatory ligands. 29 Consequently, we propose that local increases in sIL6R after neutrophil infiltration act to sequester IL6 generated early in the inflammatory response by stromal tissue cells. Generation of sIL6R is therefore the rate-limiting step for activation events governed by IL6 transsignaling within the air pouch.…”

Section: Discussionmentioning

confidence: 95%

“…We also considered the position of the ␤-globin intron present in the transgenic construct under the control of the PEPCK-promotor. 29 As shown in Figure 1A, the codon-optimized and nonoptimized sgp130Fc cDNA was cloned either upstream or downstream of the ␤-globin intron. Individual constructs were subsequently transfected into HepG2 cells and sgp130Fc expression gauged by Western blot analysis of sgp130Fc precipitated from the culture supernatants.…”

Section: Resultsmentioning

confidence: 99%

“…For the expression of the transgene, we used the liver-specific PEPCK promoter, which we had used before to express the sIL6R in transgenic mice and that had led to microgram expression levels in the plasma of the animals. 29,37 In mammals, gluconeogenesis does not occur until birth and is paralleled by the expression of the PEPCK gene. 38 Therefore, expression of the sgp130Fc transgene driven by the PEPCK promoter is only expressed after birth of the animals and did not influence embryonic development.…”

Section: Discussionmentioning

confidence: 99%

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Transgenic blockade of interleukin 6 transsignaling abrogates inflammation

Rabe

Chalaris

May

et al. 2008

Blood

226

208

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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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Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Transgenic blockade of interleukin 6 transsignaling abrogates inflammation

Rabe

Chalaris

May

et al. 2008

Blood

226

208

View full text Add to dashboard Cite

show abstract

“…An approach targeting IL-6R may lead to blocking of both its membrane-bound and soluble forms, thereby yielding an efficient inhibition of IL-6 activity. In addition, since binding of IL-6 to sIL-6R in an in vivo transgenic model was shown to increase the plasma half-life of IL-6 and potentiate and prolonge the biologic effects of IL-6 in vivo (66), targeting IL-6R may, by displacing IL-6 from the IL-6-sIL-6R complex, decrease the plasma half-life of the cytokine.…”

Section: Therapeutic Approaches Aimed At Inhibiting Il-6 Effectsmentioning

confidence: 99%

Targeting the interleukin‐6 receptor: A new treatment for systemic juvenile idiopathic arthritis?

Benedetti¹,

Martini²

2005

Arthritis & Rheumatism

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“…sIL-6-R together with IL-6 can stimulate cells that express only gp130 (38,76), which was named transsignaling (60,68). Furthermore, it was shown that the sIL-6-R strongly sensitizes IL-6-responsive target cells (59). transsignaling cell types that are exclusively responsive to IL-6/IL-6-R but not to IL-6 alone include hematopoietic progenitor cells (61), endothelial cells (67), osteoclasts (77), smooth muscle cells (32), and neuronal cells (39,40).…”

mentioning

confidence: 99%

Abrogation of Viral Interleukin-6 (vIL-6)-Induced Signaling by Intracellular Retention and Neutralization of vIL-6 with an Anti-vIL-6 Single-Chain Antibody Selected by Phage Display

Kovaleva

Bußmeyer

Rabe

et al. 2006

J Virol

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Human herpesvirus 8 (HHV-8) encodes several putative oncogenes, which are homologues to cellular host genes known to function in cell cycle regulation, control of apoptosis, and cytokine signaling. Viral interleukin (vIL-6) is believed to play an important role in the pathogenesis of Kaposi's sarcoma as well as primary effusion lymphoma and multicentric Castleman's disease. Therefore, vIL-6 is a promising target for novel therapies directed against HHV-8-associated diseases. By phage display screening of human synthetic antibody libraries, we have selected a specific recombinant antibody, called monoclonal anti-vIL-6 (MAV), binding to vIL-6. The epitope recognized by MAV was localized on the top of the D helix of the vIL-6 protein, which is a part of receptor binding site III. Consequently, MAV specifically inhibits vIL-6-mediated growth of the primary effusion lymphoma-derived cell line BCBL-1 and blocks STAT3 phosphorylation in the human hepatoma cell line HepG2. Since it was previously found that vIL-6 can also induce signals from within the cell, presumably within the endoplasmic reticulum, we fused the recombinant antibody MAV with the endoplasmic retention sequence KDEL (MAV-KDEL). As a result, COS-7 cells expressing MAV-KDEL and synthesizing vIL-6 ceased to secrete the cytokine. Moreover, we observed that vIL-6 that was bound to MAV-KDEL and retained in the endoplasmic reticulum did not induce STAT3 phosphorylation in HepG2 cells. We conclude that the activity of the intracellularly retained vIL-6 protein is neutralized by MAV-KDEL. Our results might represent a novel therapeutic strategy to neutralize virally encoded growth factors or oncogenes.

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The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6.

Cited by 254 publications

References 56 publications

Transgenic blockade of interleukin 6 transsignaling abrogates inflammation

Transgenic blockade of interleukin 6 transsignaling abrogates inflammation

Targeting the interleukin‐6 receptor: A new treatment for systemic juvenile idiopathic arthritis?

Abrogation of Viral Interleukin-6 (vIL-6)-Induced Signaling by Intracellular Retention and Neutralization of vIL-6 with an Anti-vIL-6 Single-Chain Antibody Selected by Phage Display

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