• Title, Summary, Keyword: IL-6/STAT3

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IL-4 Independent Nuclear Translocalization of STAT6 in HeLa Cells by Entry of Toxoplasma gondii

  • Ahn, Hye-Jin;Kim, Ji-Yeon;Nam, Ho-Woo
    • The Korean Journal of Parasitology
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    • v.47 no.2
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    • pp.117-124
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    • 2009
  • Toxoplasma gondii provokes rapid and sustained nuclear translocation of the signal transducer and activator of transcription 6 (STAT6) in HeLa cells. We observed activation of STAT6 as early as 2hr after infection with T. gondii by the nuclear translocation of fluorescence expressed from exogenously transfected pDsRed2-STAT6 plasmid and by the detection of phosphotyrosine-STAT6 in Western blot. STAT6 activation occurred only by infection with live tachyzoites but not by co-culture with killed tachyzoites or soluble T. gondii extracts. STAT6 phosphorylation was inhibited by small interfering RNA of STAT6 (siSTAT6). In view of the fact that STAT6 is a central mediator of IL-4 induced gene expression, activation of STAT6 by T. gondii infection resembles that infected host cells has been stimulated by IL-4 treatment. STAT1 was affected to increase the transcription and expression by the treatment of siSTAT6. STAT6 activation was not affected by any excess SOCS's whereas that with IL-4 was inhibited by SOCS-1 and SOCS-3. T. gondii infection induced Eotaxin-3 gene expression which was reduced by $IFN-{\gamma}$. These results demonstrate that T. gondii exploits host STAT6 to take away various harmful reactions by $IFN-{\gamma}$. This shows, for the first time, IL-4-like action by T. gondii infection modulates microbicidal action by $IFN-{\gamma}$ in infected cells.

Role of STAT3 as a Molecular Adaptor in Cell Growth Signaling: Interaction with Ras and other STAT Proteins

  • Song, Ji-Hyon;Park, Hyon-Hee;Park, Hee-Jeong;Han, Mi-Young;Kim, Sung-Hoon;Lee, Choong-Eun
    • BMB Reports
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    • v.34 no.5
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    • pp.484-488
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    • 2001
  • STATs are proteins with a dual function: signal transducers in the cytoplasm and transcriptional activators in the nucleus. Among the six known major STATs (STAT1-6), STAT3 has been implicated in the widest range of signaling pathways that regulate cell growth and differentiation. As a part of our on-going investigation on the pleiotropic functions of STAT proteins, we examined the role of STAT3 as a molecular adaptor that links diverse cell growth signaling pathways. We observed that STAT3 can be specifically activated by multiple cytokines, such as IL-3, in transformed fibroblasts and IL-4 or IFN-$\gamma$ in primary immune cells, respectively. The selective activation of STAT3 in H-ras-transformed NIH3T3 cells is associated with an increased expression of phosphoserioe STAT3 in these cells, compared to the parental cells. Notably phosphoresine-STAT3 interacts with oncogenic ras, shown by immunoprecipitation and Western blots. The results suggest the role of STAT3 in rasinduced cellular transformation as a molecular adaptor linking the Jak/STAT and Ras/MAPK pathways. In primary immune cells, IL-4 and IFN-$\gamma$ each induced (in addition to the characteristic STAT6 and STAT1 homodimers) the formation of STAT3-containing complexes that bind to GAS probes, which correspond to the $Fe{\varepsilon}$ Rll and $Fe{\gamma}$ RI promoter sequences, respectively. Since IL-4 and IFN-$\gamma$ are known to counter-regulate the expression of these genes, the ability of STAT3 to form heterodimeric complexes with STAT6 or STAT1 implies its role in the fine-tuned control of genes that are regulated by IL-4 and IFN-$\gamma$.

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Resveratrol Inhibits IL-6-Induced Transcriptional Activity of AR and STAT3 in Human Prostate Cancer LNCaP-FGC Cells

  • Lee, Mee-Hyun;Kundu, Joydeb Kumar;Keum, Young-Sam;Cho, Yong-Yeon;Surh, Young-Joon;Choi, Bu Young
    • Biomolecules & Therapeutics
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    • v.22 no.5
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    • pp.426-430
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    • 2014
  • Prostate cancer is the most frequently diagnosed cancer. Although prostate tumors respond to androgen ablation therapy at an early stage, they often acquire the potential of androgen-independent growth. Elevated transcriptional activity of androgen receptor (AR) and/or signal transducer and activator of transcription-3 (STAT3) contributes to the proliferation of prostate cancer cells. In the present study, we examined the effect of resveratrol, a phytoalexin present in grapes, on the reporter gene activity of AR and STAT3 in human prostate cancer (LNCaP-FGC) cells stimulated with interleukin-6 (IL-6) and/or dihydrotestosterone (DHT). Our study revealed that resveratrol suppressed the growth of LNCaP-FGC cells in a time- and concentration-dependent manner. Whereas the AR transcriptional activity was induced by treatment with either IL-6 or DHT, the STAT3 transcriptional activity was induced only by treatment with IL-6 but not with DHT. Resveratrol significantly attenuated IL-6-induced STAT3 transcriptional activity, and DHT- or IL-6-induced AR transcriptional activity. Treatment of cells with DHT plus IL-6 significantly increased the AR transcriptional activity as compared to DHT or IL-6 treatment alone and resveratrol markedly diminished DHT plus IL-6-induced AR transcriptional activity. Furthermore, the production of prostate-specific antigen (PSA) was decreased by resveratrol in the DHT-, IL-6- or DHT plus IL-6-treated LNCaP-FGC cells. Taken together, the inhibitory effects of resveratrol on IL-6- and/or DHT-induced AR transcriptional activity in LNCaP prostate cancer cells are partly mediated through the suppression of STAT3 reporter gene activity, suggesting that resveratrol may be a promising therapeutic choice for the treatment of prostate cancer.

STAT mRNA kinetics in the central nervous system during autoimmune encephalomyelitis in lewis rats

  • Jee, Young-heun;Hwang, In-sun;Shin, Tae-kyun;Moon, Chang-jong;Lim, Yoon-kyu;Yeo, In-kyu;Son, Hwa-young
    • Korean Journal of Veterinary Research
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    • v.44 no.2
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    • pp.163-169
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    • 2004
  • To elucidate the molecular mechanisms of autoimmune inflammation in the central nervous system, we examined the expression and localization of STAT1, STAT3, STAT4 and STAT6 molecules during experimental autoimmune encephalomyelitis (EAE) by competitive PCR. In the present study, we quantitated IL-4 and IL-12 p40 mRNA by competitive PCR in the CNS during EAE. IL-4 mRNA was found at early and peak stages. On the other hand, the IL-12 p40 mRNA level reached maximal levels at the peak stage and still found at the recovery stage of the disease. We examined the kinetics of STAT mRNA in the CNS during EAE and demonstrated that STAT1 and STAT4 mRNA reached a maximal level at the peak stage of EAE, whereas STAT3 mRNA level increased gradually to the recovery stage. STAT6 mRNA increased rapidly at the early stage followed by gradual decrease till the recovery stage. Taken together, these findings suggest that STAT4 which was probably activated by IL-12 plays a pro-inflammatory role and that STAT3 which was activated throughout the disease course seems to serve as a transducer of anti-inflammatory signals.

Extracellular Signal-regulated Kinase Activation Is Required for Serine 727 Phosphorylation of STAT3 in Schwann Cells in vitro and in vivo

  • Lee, Hyun-Kyoung;Jung, Jun-Yang;Lee, Sang-Hwa;Seo, Su-Yeong;Suh, Duk-Joon;Park, Hwan-Tae
    • The Korean Journal of Physiology and Pharmacology
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    • v.13 no.3
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    • pp.161-168
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    • 2009
  • In the peripheral nerves, injury-induced cytokines and growth factors perform critical functions in the activation of both the MEK/ERK and JAK/STAT3 pathways. In this study, we determined that nerve injury-induced ERK activation was temporally correlated with STAT3 phosphorylation at the serine 727 residue. In cultured Schwann cells, we noted that ERK activation is required for the serine phosphorylation of STAT3 by neuropoietic cytokine interleukin-6 (IL-6). Serine phosphorylated STAT3 by IL-6 was transported into Schwann cell nuclei, thereby indicating that ERK may regulate the transcriptional activity of STAT3 via the induction of serine phosphorylation of STAT3. Neuregulin-1 (NRG) also induced the serine phosphorylation of STAT3 in an ERK-dependent fashion. In contrast with the IL-6 response, serine phosphorylated STAT3 induced by NRG was not detected in the nucleus, thus indicating the non-nuclear function of serine phosphorylated STAT3 in response to NRG. Finally, we determined that the inhibition of ERK prevented injury-induced serine phosphorylation of STAT3 in an ex-vivo explants culture of the sciatic nerves. Collectively, the results of this study show that ERK may be an upstream kinase for the serine phosphorylation of STAT3 induced by multiple stimuli in Schwann cells after peripheral nerve injury.

NDRG2-mediated Modulation of SOCS3 and STAT3 Activity Inhibits IL-10 Production

  • Lee, Eun-Byul;Kim, Ae-Yung;Kang, Kyeong-Ah;Kim, Hye-Ree;Lim, Jong-Seok
    • IMMUNE NETWORK
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    • v.10 no.6
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    • pp.219-229
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    • 2010
  • Background: N-myc downstream regulated gene 2 (NDRG2) is a member of the NDRG gene family. Our previous report indicated a possible role for NDRG2 in regulating the cytokine, interleukin-10 (IL-10), which is an important immunosuppressive cytokine. Several pathways, including p38-MAPK, NF-${\kappa}B$, and JAK/STAT, are used for IL-10 production, and the JAK/STAT pathway can be inhibited in a negative feedback loop by the inducible protein, SOCS3. In the present study, we investigated the effect of NDRG2 gene expression on IL-10 signaling pathway that is modulated via SOCS3 and STAT3. Methods: We generated NDRG2-overexpressing U937 cell line (U937-NDRG2) and treated the cells with PMA to investigate the role of NDRG2 in IL-10 production. U937 cells were also transfected with SOCS3- or NDRG2-specific siRNAs to examine whether the knockdown of SOCS3 or NDRG2 influenced IL-10 expression. Lastly, STAT3 and SOCS3 induction was measured to identify the signaling pathway that was associated with IL-10 production. Results: RT-PCR and ELISA assays showed that IL-10 was increased in U937-mock cells upon stimulation with PMA, but IL-10 was inhibited by overexpression NDRG2. After PMA treatment, STAT3 phosphorylation was decreased in a time-dependent manner in U937-mock cells, whereas it was maintained in U937-NDRG2 cells. SOCS3 was markedly reduced in U937-NDRG2 cells compared with U937-mock cells. IL-10 production after PMA stimulation was reduced in U937 cells when SOCS3 was inhibited, but this effect was less severe when NDRG2 was inhibited. Conclusion: NDRG2 expression modulates SOCS3 and STAT3 activity, eventually leading to the inhibition of IL-10 production.

Synthesis of Thienopyrimidine Derivatives as Inhibitors of STAT3 Activation Induced by IL-6

  • Jang, Hyun-Jae;Kim, Sung Min;Rho, Mun-Chual;Lee, Seung Woong;Song, Yang-Heon
    • Journal of Microbiology and Biotechnology
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    • v.29 no.6
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    • pp.856-862
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    • 2019
  • A series of thienopyrimidine compounds (6Aa-g and 6Ba-d) were synthesized and characterized by NMR spectroscopy and mass spectrometry. These compounds (6Aa-g and 6Ba-d) potently inhibited STAT3 expression induced by IL-6 in a dose-dependent manner with $IC_{50}$ values of $5.73-0.32{\mu}M$. Among the prepared thienopyrimidine derivatives, 6Aa, 6Ab, 6Ba and 6Bc significantly suppressed the phosphorylation of STAT3 and ERK1/2 stimulated by IL-6 in Hep3B cells. Furthermore, the synthesized compounds might be useful remedies for the treatment of inflammatory diseases by inhibiting the action of IL-6.

Resveratrol Prevents Hormone-refractory Prostate Cancer Cell Growth via Inhibition of STAT3 Activity (STAT3 활성 억제를 유도하는 resveratrol의 호르몬 불응성 전립선 암 예방 효과)

  • Cho, Seok-Cheol;Choi, Bu Young
    • Korean Journal of Food Science and Technology
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    • v.46 no.4
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    • pp.516-521
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    • 2014
  • The mechanisms underlying the refractory effects of flutamide, a first-line oral anti-androgen drug, have not been entirely elucidated. In the present study, we investigated the mechanism of flutamide-induced hormone-refractory prostate cancer cell growth and its modulation by resveratrol, a phytoalexin present in grapes. Resveratrol significantly attenuated interleukin 6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT3) transcriptional activity and dihydrotestosterone (DHT) or IL-6-induced prostate-specific antigen (PSA) transcriptional activity. Furthermore, compared to treatment with DHT or IL-6 alone, combination treatment of cells significantly increased PSA transcriptional activity, and resveratrol markedly diminished DHT plus IL-6-induced STAT3 and PSA transcriptional activities. Thus, the inhibitory effects of resveratrol on IL-6-, DHT-, and flutamide-induced hormone-refractory prostate cancer cell growth are partly mediated by the suppression of STAT3 reporter gene activity, suggesting that resveratrol represents a promising therapy for prostate cancer.

Janus Kinase 2 Inhibitor AG490 Inhibits the STAT3 Signaling Pathway by Suppressing Protein Translation of gp130

  • Seo, In-Ae;Lee, Hyun-Kyoung;Shin, Yoon-Kyung;Lee, Sang-Hwa;Seo, Su-Yeong;Park, Ji-Wook;Park, Hwan-Tae
    • The Korean Journal of Physiology and Pharmacology
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    • v.13 no.2
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    • pp.131-138
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    • 2009
  • The binding of interleukin-6 (IL-6) cytokine family ligands to the gp130 receptor complex activates the Janus kinase (JAK)/ signal transducer and activator of transcription 3 (STAT3) signal transduction pathway, where STA T3 plays an important role in cell survival and tumorigenesis. Constitutive activation of STAT3 has been frequently observed in many cancer tissues, and thus, blocking of the gp130 signaling pathway, at the JAK level, might be a useful therapeutic approach for the suppression of STAT3 activity, as anticancer therapy. AG490 is a tyrphostin tyrosine kinase inhibitor that has been extensively used for inhibiting JAK2 in vitro and in vivo. In this study, we demonstrate a novel mechanism associated with AG490 that inhibits the JAK/STAT3 pathway. AG490 induced downregulation of gp130, a common receptor for the IL-6 cytokine family compounds, but not JAK2 or STAT3, within three hours of exposure. The downregulation of gp130 was not caused by enhanced degradation of gp130 or by inhibition of mRNA transcription. It most likely occurred by translation inhibition of gp130 in association with phosphorylation of the eukaryotic initiation factor-2 a. The inhibition of protein synthesis of gp130 by AG490 led to immediate loss of mature gp130 in cell membranes, due to its short half-life, thereby resulting in reduction in the STAT3 response to IL-6. Taken together, these results suggest that AG490 blocks the STAT3 activation pathway via a novel pathway.

Tyrphostin ErbB2 Inhibitors AG825 and AG879 Have Non-specific Suppressive Effects on gp130/ STAT3 Signaling

  • Lee, Hyun-Kyoung;Seo, In-Ae;Lee, Sang-Hwa;Seo, Su-Young;Kim, Kyung-Sup;Park, Hwan-Tae
    • The Korean Journal of Physiology and Pharmacology
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    • v.12 no.5
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    • pp.281-286
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    • 2008
  • Although the interaction between gp130 and the ErbB family has frequently been shown in cancer cells, the mechanism of this interaction remains unclear and controversial. In the present study, we found that specific tyrphostin inhibitors of ErbB2 (AG825 and AG879), but not ErbB1 inhibitor (AG1478), suppressed IL-6-induced tyrosine phosphorylation of STAT3 in schwannoma cells. However, biochemical evidence for transactivation of ErbB2 by IL-6 was not observed. Additionally, the inhibition of ErbB2 expression, with either a specific RNAi or transfection of an ErbB2 mutant lacking the intracellular domain did not inhibit the IL-6-induced tyrosine phosphorylation of STAT3. Thus, it seems that tyrphostins, which are known as specific inhibitors of the ErbB2 kinase, may have non-specific suppressive effects on the IL-6/STAT3 pathway.