Blockade of Interleukin-6 Receptor Alleviates Disease in Mouse Model of Scleroderma

Kitaba, Shun; Murota, Hiroyuki; Terao, Mineko; Azukizawa, Hiroaki; Terabe, Fumitaka; Shima, Yoshihito; Fujimoto, Minoru; Tanaka, Toshio; Naka, Tetsuji; Kishimoto, Tadamitsu; Katayama, Ichiro

doi:10.1016/j.ajpath.2011.09.013

Cited by 119 publications

(89 citation statements)

References 32 publications

(20 reference statements)

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“…Moreover, lung tissue pathology, on day 21 after bleomycin treatment, showed significant fibrotic changes with increased collagen content in WT mice compared with IL-6 KO mice (p < 0.05) [14]. Kitaba et al obtained similar results with IL-6 KO bleomycin mice having reduced dermal fibrosis comparing with the WT mice [15].…”

Section: B-cell Depletionsupporting

confidence: 64%

Biological Therapy in Systemic Sclerosis

Caetano¹,

Oliveira²,

Alves³

2017

Systemic Sclerosis

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Systemic sclerosis is the autoimmune connective tissue disease with the highest morbidity and mortality, through the combination of inflammation, vasculopathy and fibrosis leading to severe internal organ involvement. Currently, there are no approved diseasemodifying therapies, and treatment is based on organ-specific treatment and broad immunosuppression, with disappointing long-term results in most cases. Recent research has helped to improve knowledge of the pathogenesis of systemic sclerosis and to optimize treatment based on specific physiopathological targets, and a new era of biological agents in systemic sclerosis has now begun. Promising results are emerging from targeting specific cytokine signalling, especially IL-6, and cellular subpopulations such as B cells, with anti-CD20 therapy, and T-cells, with inhibition of T-cell co-stimulation. Other approaches under evaluation are based on the modulation of profibrotic pathways by anti-TGF-β agents. In this chapter, we discuss the available evidence to support the use of each biological agent in systemic sclerosis based on data from basic and translational research and on results from clinical studies.

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Section: B-cell Depletionsupporting

confidence: 64%

Biological Therapy in Systemic Sclerosis

Caetano¹,

Oliveira²,

Alves³

2017

Systemic Sclerosis

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“…24 IL-6 produced from dermal fibroblasts also contribute to fibrosis by activating fibroblasts to myofibroblasts, which are known to produce collagen. 25 In this study, we found that OCT significantly suppressed the expression of not only TGFb-induced POSTN expression, but also IL-4 and IL-13-induced POSTN expression in dermal fibroblasts. As POSTN is an essential matricellular protein in skin sclerosis of SSc patients and in a BLM-induced scleroderma model, 15 we hypothesize that OCT suppresses dermal sclerosis in part by downregulating the expression of POSTN.…”

Section: Discussionmentioning

confidence: 67%

A vitamin D analog inhibits Th2 cytokine- and TGFβ -induced periostin production in fibroblasts: a potential role for vitamin D in skin sclerosis

Terao

Yang

Matsumura

et al. 2015

Dermato-Endocrinology

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& Ichiro Katayama (2015) A vitamin D analog inhibits Th2 cytokine-and TGFβ -induced periostin production in fibroblasts: a potential role for vitamin D in skin sclerosis, Dermato-Endocrinology, 7:1, e1010983, DOI: 10.1080DOI: 10. /19381980.2015 Scleroderma is an autoimmune disease characterized by extracellular matrix deposition and inflammation. Topical vitamin D analogs have been reported as effective treatments for scleroderma. We previously reported that a matricellular protein, periostin (POSTN), contributes to pathogenesis of scleroderma as POSTN knockout mice were resistant to bleomycin (BLM)-induced scleroderma. We investigated whether a vitamin D analog affects the expression of POSTN in dermal fibroblasts and in a BLM-induced scleroderma model. The vitamin D analog, maxacalcitol ), was applied to dermal fibroblasts and POSTN expression was measured. The effect of OCT on Th2 cytokine-and TGFb-induced POTSN and Collagen 1 a 1 (Col1A1) expression was also assessed. In vivo, OCT was administered to BLM-induced scleroderma model and outcomes were determined by dermal thickness, collagen density and POSTN expression. Treatment with OCT significantly decreased POSTN expression in dermal fibroblasts. Th2 cytokine-and TGFb-induced expression of POSTN and Col1A1 was also suppressed by OCT. In vivo, OCT administration decreased the density of collagen bundles and POSTN expression in a BLM-induced scleroderma model. In addition to the previously reported immunosuppressive effect, the vitamin D analog OCT might be effective to treat scleroderma, in part through inhibition of Th2 cytokine-and TGFb-induced POSTN expression.

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“…Second, IL-6 promotes collagen production and expression of α-smooth muscle actin by dermal fi broblasts, as well as endothelial cell activation and apoptosis in endothelial cell-neutrophil co-cultures. Moreover, in models of SSc induced by bleomycin, IL-6 blockade by administration of anti-IL-6R Ab suppresses myofi broblast activation, resulting in reduced dermal fi brosis [ 58 ]. We observed the benefi cial effects of tocilizumab for two patients with SSc [ 59 ].…”

Section: Effi Cacy Of Tocilizumab In Other Autoimmune Infl Ammatory Dmentioning

confidence: 59%

IL-6: A New Era for the Treatment of Autoimmune Inflammatory Diseases

Kishimoto

Kang

Tanaka

2015

Innovative Medicine

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A series of studies have revealed that IL-6 has pleiotropic activity in various cells and that its deregulated expression is responsible for the development of multiple autoimmune infl ammatory diseases. A humanized antibody against the IL-6 receptor, tocilizumab, has exhibited outstanding therapeutic effi cacy against rheumatoid arthritis, juvenile idiopathic arthritis, Castleman's disease, and other autoimmune infl ammatory diseases, leading to its clinical use for treatment of several diseases. These fi ndings indicate that overproduction of IL-6 is responsible for the pathogenesis of autoimmune infl ammatory diseases, in which an imbalance between Th17 cells and regulatory T cells and autoantibodies play central roles. Recent studies have suggested that IL-6 blockade therapy can rectify these underlying immunological abnormalities in autoimmunity. However, the causes of deregulated IL-6 production in these diseases remain unknown. A novel IL-6-regulating molecule, Arid5a, specifi cally stabilizes IL-6 mRNA and sustains its overproduction; thus, Arid5a plays an important role in promoting infl ammation and autoimmune diseases. Indeed, in Arid5a-knockout mice, experimental autoimmune encephalomyelitis does not develop, and lipopolysaccharide stimulation does not induce elevated expression of IL-6. Arid5a can counteract the destabilizing effect of a regulatory RNase, Regnase-1, on IL-6 mRNA; Regnase-1 knockout mice spontaneously develop various fatal autoimmune diseases. Further analyses of these RNA-binding proteins as well as other regulatory molecules for IL-6 expression are expected to elucidate the molecular mechanisms underlying deregulated synthesis of IL-6, and facilitate investigations of the pathogenesis of specifi c diseases.

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Blockade of Interleukin-6 Receptor Alleviates Disease in Mouse Model of Scleroderma

Cited by 119 publications

References 32 publications

Biological Therapy in Systemic Sclerosis

Biological Therapy in Systemic Sclerosis

A vitamin D analog inhibits Th2 cytokine- and TGFβ -induced periostin production in fibroblasts: a potential role for vitamin D in skin sclerosis

IL-6: A New Era for the Treatment of Autoimmune Inflammatory Diseases

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