Functional characterization of a soluble gp130 isoform and its therapeutic capacity in an experimental model of inflammatory arthritis

Richards, Peter J.; Nowell, Mari Ann; Horiuchi, Sankichi; McLoughlin, Rachel M.; Fielding, Ceri Alan; Grau, Sandra; Yamamoto, Naoki; Ehrmann, Michael; Rose-John, Stefan; Williams, Anwen Siân; Topley, Nicholas; Jones, Simon A.

doi:10.1002/art.21818

Cited by 94 publications

(74 citation statements)

References 34 publications

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“…48 These results strongly indicate a much more global role for IL6 transsignaling in the regulation of the immune system in which IL6 acting via the membrane-bound IL6R governing the hepatic acute-phase reaction 49 and regulating B-cell stimulation 50 and IL6 acting via the soluble IL6R is primarily activated under pathophysiologic conditions. [11][12][13][14][15][16] In this respect it is interesting that thermal stress in the range of fever temperatures increased the expression of intercellular adhesion molecule 1 (ICAM1) exclusively in high endothelial venules, which was accompanied by increased lymphocyte trafficking across high endothelial venules, and that the thermal induction of ICAM1 was governed by the IL6-transsignaling pathway. 51 The sgp130Fc transgenic mice will be challenged in more prolonged inflammatory events such as T-cell effector/memory functions and chronic disease progression.…”

Section: Discussionmentioning

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.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…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.…”

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Transgenic blockade of interleukin 6 transsignaling abrogates inflammation

Rabe

Chalaris

May

et al. 2008

Blood

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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: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Transgenic blockade of interleukin 6 transsignaling abrogates inflammation

Rabe

Chalaris

May

et al. 2008

Blood

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230

208

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“…Histology sections were scored by 2 independent observers who were blinded to the experiments. An established histology scoring method was used (1,(23)(24)(25)(26), in which synovial hyperplasia was scored 0-3, inflammatory cells within the synovial tissue was scored 0-5, inflammatory cells within the synovial cavity was scored 0-3, and articular cartilage/subchondral bone erosion was scored 0-3.…”

Section: Methodsmentioning

confidence: 99%

Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

Evans

Williams

Hayes

et al. 2011

Arthritis & Rheumatism

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Objective. To assess the ability of pre-B cell colony-enhancing factor (PBEF) to regulate inflammation and degradative processes in inflammatory arthritis, using the small molecule inhibitor APO866 in human fibroblasts in vitro and in murine collageninduced arthritis (CIA).Methods. Enzyme-linked immunosorbent assays were used to examine regulation of expression of metalloproteinases and chemokines in human fibroblasts. The role of PBEF was further examined using APO866 in mice with CIA, with effects on disease activity assessed using radiography, histology, in vivo imaging, and quantitative polymerase chain reaction (qPCR).Results. In vitro activation of human fibroblasts with PBEF promoted expression of matrix metalloproteinase 3 (MMP-3), CCL2, and CXCL8, an effect inhibited by APO866. In mice with CIA, early intervention with APO866 inhibited synovial inflammation, including chemokine-directed leukocyte infiltration, and reduced a systemic marker of inflammation, serum hyaluronic acid. APO866 blockade led to reduced expression of MMP-3 and MMP-13 in joint extracts and to a reduction in a systemic marker of cartilage erosion, serum cartilage oligomeric matrix protein. Radiologic images revealed that APO866 protected against bone erosion, while qPCR demonstrated inhibition of RANKL expression. In mice with established disease, APO866 reduced synovial inflammation and cartilage destruction, and halted bone erosion. In addition, APO866 reduced the activity of MMP-3, CCL2, and RANKL in vivo, and inhibited production of CCL2 and RANKL in synovial explants from arthritic mice, a result that was reversed with nicotinamide mononucleotide.Conclusion. These findings confirm PBEF to be an important regulator of inflammation, cartilage catabolism, and bone erosion, and highlight APO866 as a promising therapeutic agent for targeting PBEF activity in inflammatory arthritis.Pre-B cell colony-enhancing factor (PBEF) represents an inflammatory mediator that exerts enzymatic activities and is highly expressed within the synovial tissue and plasma of patients with rheumatoid arthritis (1,2). In this respect, PBEF acts as a nicotinamide phosphoribosyltransferase (referred to as NAMPT) that controls NAD biosynthesis by catalyzing nicotinamide with 5-phosphoribosyl-1-pyrophosphate (3-5). Conversely, exogenous PBEF is also described as an adipocytokine (referred to as visfatin), and can regulate cellular processes via activation of transcriptional events through NF-B, phosphatidylinositol 3-kinase, and MAP kinase (6-8). Several groups have shown that PBEF interacts with the insulin receptor (8-10); however, this notion remains controversial (11,12), and it may be that PBEF signals through an alternative signaling route. It is also unlikely that this signaling effect is attributable to the endotoxin that may be present in PBEF preparations, since coincubation with polymixin B shows no abrogation of PBEF signaling (6,10,13).In vitro activation of signaling pathways by PBEF has been shown to regulate the expression of metalloproteinases...

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