IL-2 Inhibition of Th17 Generation Rather Than Induction of Treg Cells Is Impaired in Primary Sjögren’s Syndrome Patients

Luo, Jing; Ming, Bingxia; Zhang, Cai; Deng, Xiaofei; Li, Pingfei; Wei, Zhengping; Xia, Yu; Jiang, Kan; Ye, Hong; Ma, Wanli; Liu, Zheng; Li, Hua-Bin; Yang, Xun; Dong, Lingli

doi:10.3389/fimmu.2018.01755

Cited by 44 publications

(31 citation statements)

References 37 publications

(43 reference statements)

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“…Constitutive activated STAT3 in mice lead to chronic corneal inflammation and epithelial squamous metaplasia. 17 More importantly, enhanced STAT3 activation was also found in the salivary glands of Sjögren's syndrome patients, 35 which suggests that targeting STAT3 inhibition may be effective for dry eye disease. Consistently, here, direct evidence is provided to confirm the abnormal STAT3 activation in the ocular surface epithelium in three dry eye mouse models, including BAC treatment, LGE, and Tabby mice.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Effects of STAT3 Inhibition on Experimental Murine Dry Eye

Wang

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To investigate the therapeutic effects of targeting signal transducer and activator of transcription-3 (STAT3) activation on the ocular surface damage of dry eye in mice. METHODS. Adult Balb/C and C57BL/6 mice with benzalkonium chloride (BAC) treatment, lacrimal gland excision, and meibomian gland dysfunction were used as dry eye models. The levels of phosphorylated STAT3 (p-STAT3) were detected with immunofluorescence staining and Western blotting. STAT3 inhibition was performed by topical application of STAT3 inhibitor S3I-201. Corneal epithelial barrier function, tear production, and conjunctival goblet cell density were quantified with fluorescein sodium staining, phenol red cotton test, and histochemical staining. The expressions of matrix metalloproteinase (MMP)-3/9, TUNEL, and inflammation cytokines were assessed with immunofluorescence staining, qPCR, and ELISA assays. The therapeutic effect of S3I-201 was further compared with the Janus kinase inhibitor tofacitinib and ruxolitinib. RESULTS. Elevated levels of nuclear p-STAT3 were detected in the corneal and conjunctival epithelium of three dry eye models. Topical application of S3I-201 improved corneal epithelial barrier function, increased tear production and conjunctival goblet cell density in BACinduced dry eye mice. Moreover, S3I-201 decreased the expression of MMP-3/9, suppressed the apoptosis of corneal and conjunctival epithelial cells, and reduced the levels of IL-1b, IL-6, IL-17A, and IFN-c. Compared with tofacitinib and ruxolitinib, the STAT3 inhibitor S3I-201 showed superior improvement of tear production and inflammatory cytokine expression in lacrimal gland. CONCLUSIONS. Elevated STAT3 activation is involved in the pathogenesis of dry eye, while targeting STAT3 effectively alleviates BAC-induced ocular surface damage.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Effects of STAT3 Inhibition on Experimental Murine Dry Eye

Wang

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…From our data, lenalidomide also seems to have effects on the frequency of IL-17A-, TNF-a-, and IFN-g-producing cells. The reduction in IL-17A + CD4 + T cells could be due to the increase of IL-2 in the cell culture supernatants, which has been shown to inhibit the differentiation of Th17 cells (6,44,45). IL-2 has also been shown to increase the expression of IFN-g in human CD4 + T cells (46,47) and TNF-a expression in mouse CD8 + T cells (48).…”

Section: Discussionmentioning

confidence: 99%

IKZF3/Aiolos Is Associated with but Not Sufficient for the Expression of IL-10 by CD4+ T Cells

Ridley

Fleskens

Roberts

et al. 2020

The Journal of Immunology

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The expression of anti-inflammatory IL-10 by CD4 + T cells is indispensable for immune homeostasis, as it allows T cells to moderate their effector function. We previously showed that TNF-a blockade during T cell stimulation in CD4 + T cell/monocyte cocultures resulted in maintenance of IL-10-producing T cells and identified IKZF3 as a putative regulator of IL-10. In this study, we tested the hypothesis that IKZF3 is a transcriptional regulator of IL-10 using a human CD4 + T cell-only culture system. IL-10 + CD4 + T cells expressed the highest levels of IKZF3 both ex vivo and after activation compared with IL-10-CD4 + T cells. Pharmacological targeting of IKZF3 with the drug lenalidomide showed that IKZF3 is required for anti-CD3/CD28 mAbmediated induction of IL-10 but is dispensable for ex vivo IL-10 expression. However, overexpression of IKZF3 was unable to upregulate IL-10 at the mRNA or protein level in CD4 + T cells and did not drive the transcription of the IL10 promoter or putative local enhancer constructs. Collectively, these data indicate that IKZF3 is associated with but not sufficient for IL-10 expression in CD4 + T cells.

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“…IL‐2 is involved in cell fibrosis, immunoregulation, development and other biological behaviors via activation of the STAT3 and NK‐κB signaling pathways (Jung et al., ; Luo et al., ; Mitrokhin, Gorbacheva, Mladenov, & Kamkin, ; Park et al., ; Wu et al., ). In our study, IL‐2 could activate STAT3 and NK‐κB signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐2 induces extracellular matrix synthesis and TGF‐β2 expression in retinal pigment epithelial cells

Jing

Wen

et al. 2019

Dev Growth Differ

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Macular fibrosis is a vital obstacle of vision acuity improvement of age‐related macular degeneration patients. This study was to investigate the effects of interleukin 2 (IL‐2) on epithelial‐mesenchymal transition (EMT), extracellular matrix (ECM) synthesis and transforming growth factor β2 (TGF‐β2) expression in retinal pigment epithelial (RPE) cells. 10 μg/L IL‐2 was used to induce fibrosis in RPE cells for various times. Western blot was used to detect the EMT marker α‐smooth muscle actin (α‐SMA), ECM markers fibronectin (Fn) and type 1 collagen (COL‐1), TGF‐β2, and the activation of the JAK/STAT3 and NF‐κB signaling pathway. Furthermore, JAK/STAT3 and NF‐κB signaling pathways were specifically blocked by WP1066 or BAY11‐7082, respectively, and the expression of α‐SMA, COL‐1, Fn and TGF‐β2 protein were detected. Wound healing and Transwell assays were used to measure cell migration ability of IL‐2 with or without WP1066 or BAY11‐7082. After induction of IL‐2, the expressions of Fn, COL‐1, TGF‐β2 protein were significantly increased, and this effect was correlated with IL‐2 treatment duration, while α‐SMA protein expression did not change significantly. Both WP1066 and BAY11‐7082 could effectively downregulate the expression of Fn, COL‐1 and TGF‐β2 induced by IL‐2. What's more, both NF‐κB and JAK/STAT3 inhibitors could suppress the activation of the other signaling pathway. Additionally, JAK/STAT3 inhibitor WP1066 and NF‐κB inhibitor BAY 11‐7082 could obviously decrease RPE cells migration capability induced by IL‐2. IL‐2 promotes cell migration, ECM synthesis and TGF‐β2 expression in RPE cells via JAK/STAT3 and NF‐κB signaling pathways, which may play an important role in proliferative vitreoretinopathy.

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IL-2 Inhibition of Th17 Generation Rather Than Induction of Treg Cells Is Impaired in Primary Sjögren’s Syndrome Patients

Cited by 44 publications

References 37 publications

Therapeutic Effects of STAT3 Inhibition on Experimental Murine Dry Eye

Therapeutic Effects of STAT3 Inhibition on Experimental Murine Dry Eye

IKZF3/Aiolos Is Associated with but Not Sufficient for the Expression of IL-10 by CD4+ T Cells

Interleukin‐2 induces extracellular matrix synthesis and TGF‐β2 expression in retinal pigment epithelial cells

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