Asymmetric action of STATs drive transcriptional outputs and cytokine specificity.

• Project/Area Number: 25893032
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Immunology
• Research Institution: Chiba University
• Principal Investigator: KIYOSHI Hirahara 千葉大学, 医学(系)研究科(研究院), 客員准教授 (00707193)
• Project Period (FY): 2013-08-30 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 免疫学 / 遺伝子 / シグナル伝達 / サイトカイン

Outline of Final Research Achievements

Interleukin-6 (IL-6) and IL-27 signal through a shared receptor subunit and employ the same downstream STAT transcription proteins,but yet are ascribed unique and overlapping functions. To evaluate the specificity and redundancy for these cytokines, we quantified their global transcriptomic changes and determined the relative contributions of STAT1 and STAT3 using genetic models and ChIP-seq approaches. We found an extensive overlap of the transcriptomes induced by IL-6 and IL-27 and few examples in which the cytokines acted in opposition. Using STAT-deficient cells and T cells from patients with gain-of-function STAT1 mutations, we demonstrated that STAT3 is responsible for the overall transcriptional output driven by both cytokines, whereas STAT1 is the principal driver of specificity. STAT1 cannot compensate in the absence of STAT3 and, in fact, much of STAT1 binding to chromatin is STAT3 dependent. Thus, STAT1 shapes the specific cytokine signature superimposed upon STAT3's action.

Research Products

• [Journal Article] Interleukin-25 and mucosal T cells in noneosinophilic and eosinophilic chronic rhinosinusitis (2015)
  • Author(s): Iinuma T, Okamoto Y, Yamamoto H, Inamine-Sasaki A, Ohki Y, Sakurai T, Funakoshi U, Yonekura S, Sakurai D, Hirahara K, Nakayama T
  • Journal Title: Ann Allergy Asthma Immunol Volume: 114 Issue: 4 Pages: 289-298
  • DOI: 10.1016/j.anai.2015.01.013
  • Peer Reviewed
• [Journal Article] The Interleukin-33-p38 Kinase Axis Confers Memory T Helper 2 Cell Pathogenicity in the Airway. (2015)
  • Author(s): Endo, Y., Hirahara, K., Iinuma, T., Shinoda, K., Tumes, D. J., Asou, H. K., Matsugae, N., Obata-Ninomiya, K., Yamamoto, H., Motohashi, S., Oboki, K, Nakae, S., Saito, H., Okamoto, Y., and Nakayama, T.
  • Journal Title: Immunity Volume: 42(2) Issue: 2 Pages: 294-308
  • DOI: 10.1016/j.immuni.2015.01.016
  • Peer Reviewed / Open Access
• [Journal Article] Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells. (2014)
  • Author(s): Watanabe, Y., Onodera, A., Kanai, U., Ichikawa, T., Obata-Ninomiya, K., Wada, T., Kiuchi, M., Iwamura, C., Tumes, DJ., Shinoda, K., Yagi, R., Motohashi, S., Hirahara, K. and Nakayama, T.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 111(35) Issue: 35 Pages: 12829-34
  • DOI: 10.1073/pnas.1321245111
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptional and epigenetic networks of helper T and innate lymphoid cells. (2014)
  • Author(s): Shih HY, Sciumè G, Poholek A, Vahedi G, Hirahara K, Villarino AV, Bonelli M, Bosselut R, Kanno Y, Muljo SA, O'Shea JJ
  • Journal Title: Immunol Rev. Volume: 261 Issue: 1 Pages: 23-49
  • DOI: 10.1111/imr.12208
  • Peer Reviewed
• [Journal Article] Cross-talk between RORγt+ innate lymphoid cells and intestinal macrophages induces mucosal IL-22 production in Crohn's disease (2014)
  • Author(s): Mizuno S, Mikami Y, Kamada N, Handa T, Hayashi A, Sato T, Matsuoka K, Matano M, Ohta Y, Sugita A, Koganei K, Sahara R, Takazoe M, Hisamatsu T, Kanai T
  • Journal Title: Inflamm Bowel Dis. Volume: 20 Pages: 1426-1434
  • DOI: 10.1007/82_2014_371
  • ISBN: 9783319073941, 9783319073958
  • Peer Reviewed
• [Journal Article] A mouse model of HIES reveals pro and anti-inflammatory functions of STAT3. (2014)
  • Author(s): Steward-Tharp SM, Laurence A, Kanno Y, Kotlyar A, Villarino AV, Sciume G, Kuchen S, Resch W, Wohlfert E, Jiang K, Hirahara K, Vahedi G, Sun HW, Feigenbaum L, Milner JD, Holland SM, Casellas R, Powrie F, and O'Shea JJ
  • Journal Title: Blood Volume: 印刷中 Issue: 19 Pages: 2978-2987
  • DOI: 10.1182/blood-2013-09-523167
  • Peer Reviewed
• [Journal Article] エピジェネティクス(Epigenetics)と呼吸器疾患 (2014)
  • Author(s): 平原 潔、中山 俊憲
  • Journal Title: Respiratory Medical Research Volume: 2 Pages: 63-65
• [Journal Article] Th2細胞分化制御の新知見とアレルギー発症の新概念 (2014)
  • Author(s): 平原 潔、中山 俊憲
  • Journal Title: 実験医学増刊 Volume: 32 Pages: 70-74
• [Journal Article] Type I IFN Induces Binding of STAT1 to Bcl6: Divergent Roles of STAT Family Transcription Factors in the T Follicular Helper Cell Genetic Program. (2014)
  • Author(s): Nakayamada S, Poholek AC, Lu KT, Takahashi H, Kato M, Iwata S, Hirahara K, Cannons JL, Schwartzberg PL, Vahedi G, Sun HW, Kanno Y, O'Shea JJ.
  • Journal Title: J Immunol. Volume: 192 Issue: 5 Pages: 2156-2166
  • DOI: 10.4049/jimmunol.1300675
  • Peer Reviewed
• [Journal Article] Pathogenic memory type Th2 cells in allergic inflammation (2014)
  • Author(s): Endo, Y., Hirahara, K., Yagi, R., Tumes, D. J., and Nakayama, T.
  • Journal Title: Trends Immunol Volume: 35(2) Issue: 2 Pages: 69-78
  • DOI: 10.1016/j.it.2013.11.003
  • Peer Reviewed
• [Journal Article] Gata3/Ruvbl2 complex regulates T helper 2 cell proliferation via repression of Cdkn2c expression. (2013)
  • Author(s): Hosokawa H, Tanaka T, Kato M, Tohyama H, Hanazawa A, Tamaki Y, Hirahara K, Sakikawa I, Morita A, Nagira M, Suzuki Y, Nakayama T.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 110(46) Issue: 46 Pages: 18626-18631
  • DOI: 10.1073/pnas.1311100110
  • Peer Reviewed
• [Presentation] Asymmetry of STAT action to define specificity and redundancy of IL-27 and IL-6 signals. (2014)
  • Author(s): Hirahara K, Wada T, Nakayama T, O’Shea JJ
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都国際会館（京都府、京都市）
  • Year and Date: 2014-12-11
• [Presentation] アレルギー性炎症の病態形成における多様なヘルパーT細胞サブセットの役割 (2014)
  • Author(s): 平原 潔
  • Organizer: 第10回千葉小児感染・アレルギー懇話会
  • Place of Presentation: 京成ホテルミラマーレ（千葉県、千葉市）
  • Year and Date: 2014-11-20
  • Invited
• [Presentation] Crucial roles for CD4+ helper T cells at the host defense mucosal barriers of the lung. (2014)
  • Author(s): Hirahara K and Nakayama T
  • Organizer: 第87回日本生化学大会
  • Place of Presentation: 京都国際会館（京都府、京都市）
  • Year and Date: 2014-10-15
  • Invited
• [Presentation] CD4 T細胞を介した免疫恒常性の制御およびその破綻による慢性真菌感染症について (2014)
  • Author(s): 平原 潔
  • Organizer: 真菌医学研究センターMonthlyセミナー
  • Place of Presentation: 千葉大学真菌医学研究センター(千葉県、千葉市）
  • Year and Date: 2014-10-07
  • Invited
• [Presentation] Asymmetry of STAT Action to Define Specificity and Redundancy of IL-27 and IL-6 Signals. (2014)
  • Author(s): Hirahara K, Kanno Y , Nakayama T and O’Shea JJ
  • Organizer: The 2nd Symposium of International Immunological Memory and Vaccine Forum
  • Place of Presentation: La Jolla (USA)
  • Year and Date: 2014-08-26
  • Invited
• [Presentation] Asymmetry of STAT action to define specificity and redundancy of IL-27 and IL-6 signals. (2014)
  • Author(s): Hirahara K, Nakayama T, Hunter C, Hollnad S, Kanno Y, O’Shea JJ
  • Organizer: Keystone Symposia Emerging Cytokine Networks(J3)
  • Place of Presentation: Vancouver, Canada
• [Presentation] Bach2 represses effector programs to stabilize Treg-mediated immune homeostasis. (2013)
  • Author(s): Hirahara K
  • Organizer: 第42回日本免疫学会総会学術集会
  • Place of Presentation: 幕張
• [Presentation] Bach2 represses effector Programmes to stabilize Treg-mediated immune homeostasis. (2013)
  • Author(s): Hirahara K
  • Organizer: The 3rd CSI/JSI/KAI Joint Symposium on Immunology
  • Place of Presentation: Korea
  • Invited
• [Presentation] Anti-tumor effect of BCG-LM via the activation of eosinophils. (2013)
  • Author(s): Ito T, Hirahara K, Yano I, Nakayama T
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Book] 免疫・アレルギー疾患イラストレイテッド (2013)
  • Author(s): 平原潔、中山俊憲
  • Total Pages: 8
  • Publisher: 羊土社
• [Remarks] 千葉大学大学院医学研究院 免疫発生学
  • URL: http://www.m.chiba-u.ac.jp/class/meneki/