Cell type-specific roles of Jak3 in IL-2-induced proliferative signal transduction

Fujii, Hodaka

doi:10.1016/j.bbrc.2007.01.067

Cited by 6 publications

(4 citation statements)

References 27 publications

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“…This could be suggestive of Jak3 supremacy in IL-2 signal transduction in T lymphocytes. This fact has also been described by others in megacarioblastic 43 and fibroblast 44 cell lines, and in other γc cytokines like IL-4. 45 Taken together, evidence shown here reinforce the importance of cross-talk among receptor-associated Jak kinases and discards a functional redundancy in this system.…”

Section: Discussionsupporting

confidence: 82%

Specific Jak3 Downregulation in Lymphocytes Impairs γc Cytokine Signal Transduction and Alleviates Antigen-driven Inflammation In Vivo

Gómez-Valadés

Llamas

Blanch

et al. 2012

Molecular Therapy - Nucleic Acids

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Jak3, one of the four members comprising the Jak family of cytosolic tyrosine kinases, has emerged as a promising target for nontoxic immunotherapies. Although a number of Jak inhibitors has already demonstrated efficacy, they suffer from secondary effects apparently associated to their pan-Jak activity. However, whether selective Jak3 inhibition would afford therapeutic efficacy remains unclear. To address this question we have investigated the immunosuppressive potential of selective Jak3 intervention in lymphocytes using RNA interference (RNAi) technology in vitro and in vivo. Using synthetic small interference RNA (siRNA) sequences we achieved successful transfections into human and mouse primary T lymphocytes. We found that Jak3 knockdown was sufficient to impair not only interleukin-2 (IL-2) and T cell receptor (TCR)-mediated cell activation in vitro, but also antigen-triggereds welling, inflammatory cell infiltration, and proinflammatory cytokine raise in vivo. Furthermore, Jak1 (which mediates γc cytokine signaling in conjunction with Jak3) cosilencing did not provide higher potency to the aforementioned immunosuppressant effects. Our data provides direct evidences indicating that Jak3 protein plays an important role in γc cytokine and antigen-mediated T cell activation and modulates Th1-mediated inflammatory disorders, all in all highlighting its potential as a target in immunosuppressive therapies.

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Section: Discussionsupporting

confidence: 82%

Specific Jak3 Downregulation in Lymphocytes Impairs γc Cytokine Signal Transduction and Alleviates Antigen-driven Inflammation In Vivo

Gómez-Valadés

Llamas

Blanch

et al. 2012

Molecular Therapy - Nucleic Acids

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“…Previous studies have shown that IL‐2 can activate the JAK/STAT3 and NF‐κB signaling pathway in some cells (Fujii, ; Marzec et al., ). However, whether JAK/STAT3 and NF‐κB signaling pathway play important roles in RPE cells was not clear.…”

Section: Resultsmentioning

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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“…However, no reliable gene therapy effect was found in female T lymphocytes in regulating the T-cell proliferation pathway. In addition to the genes mentioned above in the article, in male T cells, the DCA–VPA treatment significantly inhibited IL12RB1 (interleukin 12 receptor beta 1 subunit), which is linked to a significant association between susceptibility to SARS-CoV-2 infection [ 130 ], IL27RB1 , whose expression is required for CD4 + and CD8 + T-cell differentiation in humans [ 131 ], JAK3 , which has a cell type-specific role in IL-2-induced proliferative signal transduction [ 132 ], and TNFRSF14 (tumor necrosis factor-related cytokine LIGHT (TNFSF14), which has proinflammatory activity, with multifaceted roles in stimulating T cells [ 133 ]. In turn, suppressing CD209 by the medicinal product could inhibit the receptor for SARS-CoV-2 from attachment onto host cells [ 134 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Combined Treatment with Sodium Dichloroacetate and Sodium Valproate on the Genes in Inflammation- and Immune-Related Pathways in T Lymphocytes from Patients with SARS-CoV-2 Infection with Pneumonia: Sex-Related Differences

Stakišaitis,

Kapočius,

Tatarūnas

et al. 2024

Pharmaceutics

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The study presents data on the anti-inflammatory effects of a combination of sodium dichloroacetate and sodium valproate (DCA–VPA) on the expression of inflammation- and immune response-related genes in T lymphocytes of SARS-CoV-2 patients. The study aimed to assess the effects of DCA–VPA on the genes of cytokine activity, chemokine-mediated signaling, neutrophil chemotaxis, lymphocyte chemotaxis, T-cell chemotaxis, and regulation of T-cell proliferation pathways. The study included 21 patients with SARS-CoV-2 infection and pneumonia: 9 male patients with a mean age of 68.44 ± 15.32 years and 12 female patients with a mean age of 65.42 ± 15.74 years. They were hospitalized between December 2022 and March 2023. At the time of testing, over 90% of sequences analyzed in Lithuania were found to be of the omicron variant of SARS-CoV-2. The T lymphocytes from patients were treated with 5 mmol DCA and 2 mmol VPA for 24 h in vitro. The effect of the DCA–VPA treatment on gene expression in T lymphocytes was analyzed via gene sequencing. The study shows that DCA–VPA has significant anti-inflammatory effects and apparent sex-related differences. The effect is more potent in T cells from male patients with SARS-CoV-2 infection and pneumonia than in females.

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Cell type-specific roles of Jak3 in IL-2-induced proliferative signal transduction

Cited by 6 publications

References 27 publications

Specific Jak3 Downregulation in Lymphocytes Impairs γc Cytokine Signal Transduction and Alleviates Antigen-driven Inflammation In Vivo

Specific Jak3 Downregulation in Lymphocytes Impairs γc Cytokine Signal Transduction and Alleviates Antigen-driven Inflammation In Vivo

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

Effects of Combined Treatment with Sodium Dichloroacetate and Sodium Valproate on the Genes in Inflammation- and Immune-Related Pathways in T Lymphocytes from Patients with SARS-CoV-2 Infection with Pneumonia: Sex-Related Differences

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