Fli1-haploinsufficient dermal fibroblasts promote skin-localized transdifferentiation of Th2-like regulatory T cells

Saigusa, Ryosuke; Asano, Yoshihide; Taniguchi, Takashi; Hirabayashi, Megumi; Nakamura, Kouki; Miura, Shunsuke; Yamashita, Takashi; Takahashi, Takehiro; Ichimura, Yohei; Toyama, Tetsuo; Yoshizaki, Ayumi; Trojanowska, Maria; Sato, Shinichi

doi:10.1186/s13075-018-1521-3

Cited by 24 publications

(22 citation statements)

References 47 publications

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“…Interleukin-33 (IL-33), a pro-inflammatory cytokine, displays immunomodulatory functions by promoting inflammatory responses and driving Th2-type immune responses [ 1 – 3 ]. IL-33 mediates its biological effects mainly through specific receptor ST2, a member of Toll like receptor family [ 2 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

IL-33 facilitates proliferation of colorectal cancer dependent on COX2/PGE2

Shi

et al. 2018

J Exp Clin Cancer Res

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BackgroundInterleukin-33 (IL-33) participates in various types of diseases including cancers. Previous studies of this cytokine in cancers mainly focused on its regulation on immune responses by which IL-33 modulated cancer progression. The IL-33 triggered signals in cancer cells remain unclear.MethodsWe analyzed IL-33 gene expression in human colorectal cancer (CRC) tissues and carried out gene enrichment analysis with TCGA Data Portal. We studied CRC proliferation in vivo by inoculating MC38 tumors in IL-33 transgenic mice. We investigated the cell proliferation in vitro with primary CRC cells isolated from fresh human CRC tissues, human CRC cell line HT-29 and mouse CRC cell line MC38. To evaluate the proliferation modulating effects of recombinant IL-33 incubation and other administrated factors, we measured tumor growth, colony formation, cell viability, and the expression of Ki67 and proliferating cell nuclear antigen (PCNA). We used several inhibitors, prostaglandin E2 (PGE2) neutralizing antibody, ST2 blocking antibody and specific shRNA expressing plasmid to study the pathway mediating IL-33-induced CRC proliferation. The IL-33 receptor ST2 in human CRC tissues was detected by immunohistochemistry staining and western blotting. The ST2-positive or negative subsets of primary CRC cells were acquired by flow cytometry sorting.ResultsWe found that IL-33 expression was correlated with the gene signature of cell proliferation in 394 human CRC samples. The MC38 tumors grew more rapidly and the tumor Ki67 and PCNA were expressed at higher levels in IL-33 transgenic mice than in wild-type mice. IL-33 promoted cell growth, colony formation and expression of Ki67 and PCNA in primary CRC cells as well as CRC cell lines. IL-33 activated cycloxygenase-2 (COX2) expression and increased PGE2 production, whereas the COX2 selective inhibitor and PGE2 neutralizing antibody abolished the proliferation promoting effect of IL-33. ST2 blockade, ST2-negative sorting, NF-κB specific inhibitor and NF-κB specific shRNA (shP65) abrogated the COX2 induction caused by IL-33.ConclusionIL-33 facilitates proliferation of colorectal cancer dependent on COX2/PGE2. IL-33 functions via its receptor ST2 and upregulates COX2 expression through NF-κB signaling. Understanding the IL-33 signal transduction in CRC cells provides potential therapeutic targets for clinical treatment.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0839-7) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

IL-33 facilitates proliferation of colorectal cancer dependent on COX2/PGE2

Shi

et al. 2018

J Exp Clin Cancer Res

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“…On the other hand, it is generally accepted that dcSSc is characterized by Th2/Th17-skewed immune polarization, especially in its active phase, 41,42 and that IL-4, IL-13 and IL-17A, which are representative cytokines produced by Th2 and Th17 cells, are involved in the development of SSc-associated tissue fibrosis. [43][44][45] Given that various types of cells, such as dermal fibroblasts, endothelial cells, keratinocytes and macrophages, coordinately generate the microenvironment preferentially promoting Th2/Th17-skewed immune polarization in fibrotic organs of SSc, 35,[46][47][48][49] it is plausible that serum CXCL14 levels are decreased in SSc patients, especially in dcSSc patients.…”

Section: Discussionmentioning

confidence: 99%

Possible association of decreased serum CXCL14 levels with digital ulcers in patients with systemic sclerosis

Fukui

Miyagawa

Hirabayashi

et al. 2019

The Journal of Dermatology

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CXCL14 serves as a chemoattractant for activated macrophages, immature dendritic cells and natural killer cells, as well as an antiangiogenic factor by preventing the migration of endothelial cells. CXCL14 also exerts an inhibitory effect on the CXCL12/CXCR4 signaling pathway, which is involved in the maintenance of T‐helper (Th)2 bias, and promotes Th1 immune response under the physiological and pathological conditions. Because CXCL14‐mediated biological processes seem to be involved in the development of systemic sclerosis (SSc), which is characterized by Th2/Th17‐skewed immune polarization and impaired neovascularization, we investigated the clinical correlation of serum CXCL14 levels in patients with this disease. Serum CXCL14 levels were significantly decreased in SSc patients compared with healthy individuals and in diffuse cutaneous SSc patients relative to limited cutaneous SSc patients. SSc patients with digital ulcers had serum CXCL14 levels significantly lower than those without. Furthermore, i.v. cyclophosphamide pulse significantly increased serum CXCL14 levels as compared with the baseline in SSc patients with interstitial lung disease successfully treated with this therapy. These results indicate that decreased CXCL14 expression may contribute to the maintenance of Th2‐skewed immune polarization and dysregulated neovascularization, both of which underlie the developmental process of SSc.

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“…In other words, IL-33 might be an important stimulator of tissue-localized loss of normal Tregs function ( 70 ). Moreover, friend leukemia virus integration 1 (Fli1) -a predisposing factor of SSc- haploinsufficiency increases Th2- and Th17-like Tregs proportions in BLM-induced pro-fibrotic skin condition, in which IL-33-producing dermal fibroblasts contribute to Th2-like Tregs trans-differentiation ( 71 ).…”

Section: Il-33/st2 Axis In Skin Fibrosismentioning

confidence: 99%

IL-33/ST2 Axis in Organ Fibrosis

2018

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Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis.

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Fli1-haploinsufficient dermal fibroblasts promote skin-localized transdifferentiation of Th2-like regulatory T cells

Cited by 24 publications

References 47 publications

IL-33 facilitates proliferation of colorectal cancer dependent on COX2/PGE2

IL-33 facilitates proliferation of colorectal cancer dependent on COX2/PGE2

Possible association of decreased serum CXCL14 levels with digital ulcers in patients with systemic sclerosis

IL-33/ST2 Axis in Organ Fibrosis

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