Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation

Seki, Yasutaka; Hayashi, Kozaburo; Matsumoto, Akira; Seki, Nobuhiko; Tsukada, Jun; Ransom, John; Naka, Tetsuji; Kishimoto, Tadamitsu; Yoshimura, Akihiko; Kubo, Masato

doi:10.1073/pnas.202477099

Cited by 191 publications

(183 citation statements)

References 28 publications

Supporting

Mentioning

170

Contrasting

Unclassified

Order By: Relevance

“…Second, this novel mechanism appears to target only the STAT6 molecule, but not the Jak1 or Jak3 molecule. Others and we have reported Jak1 and STAT6 phosphorylation was impaired in Th1 cells (3,33). More recently, Seki et al (33) described a molecular mechanism that involved SOCS5 to explain the impairments.…”

Section: Discussionmentioning

confidence: 70%

“…Others and we have reported Jak1 and STAT6 phosphorylation was impaired in Th1 cells (3,33). More recently, Seki et al (33) described a molecular mechanism that involved SOCS5 to explain the impairments. They showed that SOCS5 inhibited STAT6 phosphorylation in Th1 cells by competing with Jak1 binding to the box1 region of the IL-4R.…”

Section: Discussionmentioning

confidence: 70%

“…SOCS1 inhibits STAT6 phosphorylation in monocytes, liver cells, and B cells (30 -32). SOCS5 was shown to suppress STAT6 phosphorylation in Th1 cells (33). Whether IFN-␥ can suppress STAT6 phosphorylation in committed CD4 ϩ Th1 cells through the known classes of inhibitors is not clear.…”

Section: T Helper Type 1 Cells Are Central Immune Components Inmentioning

confidence: 99%

See 2 more Smart Citations

IFN-γ Suppresses STAT6 Phosphorylation by Inhibiting Its Recruitment to the IL-4 Receptor

Huang

Xin

Coleman

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

Polarized Th1 cells show a stable phenotype: they become insensitive to IL-4 stimulation and lose the potential to produce IL-4. Previously, we reported that IFN-γ played a critical role in stabilizing Th1 phenotype. However, the mechanism by which IFN-γ stabilizes Th1 phenotype is not clear. In this study, we compared STAT6 phosphorylation in wild-type (WT) and IFN-γ receptor knockout (IFNGR−/−) Th1 cells. We found a striking diminution of STAT6 phosphorylation in differentiated WT Th1 cells, but not in differentiated IFNGR−/− Th1 cells. The impairment of STAT6 phosphorylation in differentiated WT Th1 cells was not due to a lack of IL-4R expression or phosphorylation. Jak1 and Jak3 expression and phosphorylation were comparable in both cell types. No differential expression of suppressor of cytokine signaling 1 (SOCS1), SOCS3, or SOCS5 was observed in the two cell types. In addition, Src homology 2-containing phosphatase mutation did not affect IL-4-induced STAT6 phosphorylation in differentiated Th1 cells derived from viable motheaten (mev/mev) mice. These results led us to focus on a novel mechanism. By using a pulldown assay, we observed that STAT6 in WT Th1 cells bound less effectively to the phosphorylated IL-4R/GST fusion protein than that in IFNGR−/− Th1 cells. Our results suggest that IFN-γ may suppress phosphorylation of STAT6 by inhibiting its recruitment to the IL-4R.

show abstract

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 70%

See 1 more Smart Citation

IFN-γ Suppresses STAT6 Phosphorylation by Inhibiting Its Recruitment to the IL-4 Receptor

Huang

Xin

Coleman

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…We evaluated the expression of SOCS3, which limits the IL-12-induced STAT4 activation and consequently the Th1 program (29). Additionally, we determined the degree of SOCS5 induction, which attenuates the IL-4-mediated activation of the STAT6/GATA3 axis and thereby the Th2 program (30,31). Whereas SOCS3 expression was similarly induced on activated CD4 + T cells from both genotypes (Fig.…”

Section: Drd3 Signaling Limits Th2 Differentiationmentioning

confidence: 99%

Dopamine Receptor D3 Signaling on CD4+ T Cells Favors Th1- and Th17-Mediated Immunity

Contreras

Prado

González

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Dopamine receptor D3 (DRD3) expressed on CD4+ T cells is required to promote neuroinflammation in a murine model of Parkinson’s disease. However, how DRD3 signaling affects T cell–mediated immunity remains unknown. In this study, we report that TCR stimulation on mouse CD4+ T cells induces DRD3 expression, regardless of the lineage specification. Importantly, functional analyses performed in vivo using adoptive transfer of OVA-specific OT-II cells into wild-type recipients show that DRD3 deficiency in CD4+ T cells results in attenuated differentiation of naive CD4+ T cells toward the Th1 phenotype, exacerbated generation of Th2 cells, and unaltered Th17 differentiation. The reciprocal regulatory effect of DRD3 signaling in CD4+ T cells favoring Th1 generation and impairing the acquisition of Th2 phenotype was also reproduced using in vitro approaches. Mechanistic analysis indicates that DRD3 signaling evokes suppressor of cytokine signaling 5 expression, a negative regulator of Th2 development, which indirectly favors acquisition of Th1 phenotype. Accordingly, DRD3 deficiency results in exacerbated eosinophil infiltration into the airways of mice undergoing house dust mite–induced allergic response. Interestingly, our results show that, upon chronic inflammatory colitis induced by transfer of naive CD4+ T cells into lymphopenic recipients, DRD3 deficiency not only affects Th1 response, but also the frequency of Th17 cells, suggesting that DRD3 signaling also contributes to Th17 expansion under chronic inflammatory conditions. In conclusion, our findings indicate that DRD3-mediated signaling in CD4+ T cells plays a crucial role in the balance of effector lineages, favoring the inflammatory potential of CD4+ T cells.

show abstract

“…Предполагается роль SOCS5 (и SOCS1) в ре-гуляции цитокиновой сигнализации IL-4 и IL-13 [9]. Так, по результатам эксперимента [7], пред-полагалось, что SOCS5 может связываться с ци-топлазматической частью IL-4Rα, тем самым нарушая STAT6 сигнализацию, индуцированную IL-4 и IL-13.…”

Section: Introductionunclassified

Expression of Negative Transcription Regulators in Peripheral Blood Mononuclears in Patients With Bronchial Asthma

Lim¹,

Ivanov²,

Сорокина³

et al. 2016

Med. immunol.

View full text Add to dashboard Cite

Адрес для переписки:Минеев Валерий Николаевич ГБОУ ВПО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Министерства здравоохранения РФ 198516, Россия, Санкт-Петербург-Петродворец, Санкт-Петербургский пр., 56, кв.15. Тел.: 8 (812) 450-71-63, (921) 359-62-95. Е-mail: vnmineev@mail.ru Address for correspondence : Mineev Valeriy N. The First St. Petersburg I. Pavlov State Medical University, St. Petersburg, Russian Federation 198516, Russian Federation, St. Petersburg-Petrodvorets, Sankt-Peterburgskiy ave, 56, apt 15. Phone: 7 (812) 450-71-63, (921) 359-62-95. E-mail: vnmineev@mail // Медицинская иммунология, 2016. Т. 18, № 5. С. 451-458. doi: 10.15789/1563-0625-2016-5-451-458 © Лим В.В. и соавт., 2016 For citation: V.V. Lim, V.A. Ivanov, L.N. Sorokina, V.N. Mineev, M.A. Nyoma, V.I Immunologiya, 2016, Vol. 18, no. 5, pp. 451-458. doi: 10.15789/1563-0625-2016 Резюме. Были обследованы 60 пациентов с аллергической бронхиальной астмой (АБА) и 41 паци-ента с неаллергической бронхиальной астмой (НАБА), а также 23 практически здоровых лица. Экс-прессию мРНК SOCS5 оценивали путем проведения ПЦР с обратной транскрипцией (RT-PCR). . Trofimov "Expression of negative transcription regulators in peripheral blood mononuclears in patients with bronchial asthma", Medical Immunology (Russia)/MeditsinskayaПолученные данные показывают, что у больных бронхиальной астмой (независимо от клинико-патогенетического варианта) отмечается выраженное повышение уровня экспрессии мРНК SOCS5 по сравнению с контрольной группой (в 1,24 раза и 1,37 раза соответственно), что, по-видимому, яв-ляется результатом повышения IL-4 и IL-13 сигнализации при бронхиальной астме.Оценивая полученные данные, можно сделать выводы о том, что повышение экспрессии мРНК SOCS5 у больных БА рассматривается как протективный ответ, направленный против воспалитель-ного процесса. Выявленные нами особенности экспрессии супрессоров цитокиновой сигнализации, вероятно, могут указывать на существование нарушений негативной регуляции клеточной сигнали-зации у больных бронхиальной астмой.Полученные данные позволяют рассматривать сложность нарушений регуляции, возникающих на различных уровнях клеточной сигнализации, с позиций полифункциональности молекул семей-ства негативных регуляторов транскрипции генов SOCS1, SOCS3 и SOCS5, обеспечивающих ком-плексный контроль цитокиновой сигнализации одновременно в различных сигнальных путях. Abstract. Sixty patients with allergic bronchial asthma (ABA) and forty-one, with non-allergic bronchial asthma (NABA), as well as 23 healthy controls were under study. Expression of the SOCS5 mRNA from mononuclear blood cells was analyzed by RT-PCR. In patients with bronchial asthma, (ABA and NABA) we

show abstract

Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation

Cited by 191 publications

References 28 publications

IFN-γ Suppresses STAT6 Phosphorylation by Inhibiting Its Recruitment to the IL-4 Receptor

IFN-γ Suppresses STAT6 Phosphorylation by Inhibiting Its Recruitment to the IL-4 Receptor

Dopamine Receptor D3 Signaling on CD4+ T Cells Favors Th1- and Th17-Mediated Immunity

Expression of Negative Transcription Regulators in Peripheral Blood Mononuclears in Patients With Bronchial Asthma

Contact Info

Product

Resources

About