Mechanism of cytokine-induced cellular senescence

• Project/Area Number: 21590316
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Osaka City University
• Principal Investigator: KOJIMA Hirotada 大阪市立大学, 大学院・医学研究科, 講師 (40336772)
• Co-Investigator(Kenkyū-buntansha): NAKAJIMA Koichi 大阪市立大学, 大学院・医学研究科, 教授 (00227787)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: サイトカイン / 細胞老化 / がん / シグナル伝達

Research Abstract

Normal cells undergo senescence in response to various stresses, such as DNA damage and certain cytokines. One such cytokine, interleukin-6 (IL-6), a multifunctional cytokine, can act on multiple lineages of cells combination with soluble IL-6 receptor α (sIL-6Rα) to induce cell proliferation, differentiation and even promotion of tumorigenesis. We studied the molecular mechanisms by which IL-6 and sIL-6Rα cause premature senescence using primary human fibroblasts. Stimulation of fibroblasts cells with IL-6/sIL-6Rα sequentially caused generation of reactive oxygen species (ROS) as early as day 1, followed by DNA damage, p53 accumulation, and finally senescence. STAT3 was required for the early and late events leading to senescence, including the early-phase increase of ROS and senescence-associated secretary phenotype occurring 4 days after IL-6/sIL-6Ra stimulation. Interestingly, Insulin-like growth factor-binding protein 5 (IGFBP-5) secreted into the supernatants was identified as the STAT3-downstream molecule responsible for the IL-6/STAT3-induced ROS generation and premature senescence. IGFBP-5 was consistently expressed from the initial phase through the entire senescence process, the profile being quite different from that of senescence-associated secretary phenotype. Thus, IL-6/sIL-6R? forms a senescence-inducing circuit involving the STAT3?IGFBP5 axis as a key triggering and reinforcing component.

Research Products

• [Journal Article] The STAT3-IGFBP5 axis is critical for IL-6/gp130-induced premature senescence in human fibroblasts (2012)
  • Author(s): Kojima H, Kunimoto H, Inoue T, Nakajima K
  • Journal Title: Cell Cycle Volume: 11 Issue: 4 Pages: 730-739
  • DOI: 10.4161/cc.11.4.19172
  • Peer Reviewed
• [Journal Article] SIRT2 down-regulation in HeLa can induce p53 accumulation via p38 MAPK activation-dependent p300 decrease, eventually leading to apoptosis (2011)
  • Author(s): Li Y, Matsumori H, Nakayama Y, Osaki M, Kojima H,, Kurimasa A, Ito H, Mori S, Katoh M, Oshimura M, Inoue T
  • Journal Title: Genes Cells Volume: 16 Issue: 1 Pages: 34-45
  • DOI: 10.1111/j.1365-2443.2010.01460.x
  • Peer Reviewed
• [Journal Article] Identification of functional domains and novel binding partners of STIM proteins (2011)
  • Author(s): Saitoh N, Oritani K, Saito K, Yokota T, Ichii M, Sudo T, Fujita N, Nakajima K, Okada M, Kanakura Y
  • Journal Title: J Cell Biochem Volume: 112 Issue: 1 Pages: 147-156
  • DOI: 10.1002/jcb.22910
  • Peer Reviewed
• [Journal Article] Phospho-Ser727 of STAT3 regulates STAT3 activity by enhancing dephosphory-lation of phospho-Tyr705 largely through TC45 (2011)
  • Author(s): Ryohei Wakahara, Hiroyuki Kunimoto, Kanae Tanino, Hirotada Kojima, Akira Inoue, Haruo Shintaku and Koichi Nakajima
  • Journal Title: Genes to Cells Volume: 17 Issue: 2 Pages: 132-145
  • DOI: 10.1111/j.1365-2443.2011.01575.x
  • Peer Reviewed
• [Journal Article] SIRT2 down-regulation in HeLa can induce p53 accumulation via p38 MAPK activation-dependent p300 decrease, eventually leading to apoptosis. (2011)
  • Author(s): Li Y, Matsumori H, Nakayama Y, Osaki M, Kojima H, Kurimasa A, ItoH, Mori S, Katoh M, Oshimura M, Inoue T.
  • Journal Title: Genes Cells. Volume: 16 Pages: 34-45
  • Peer Reviewed
• [Journal Article] Identification of functional domains and novel binding partners of STIM proteins. (2011)
  • Author(s): Saitoh N, Oritani K, Saito K, Yokota T, Ichii M, Sudo T, Fujita N, Nakajima K, Okada M, Kanakura Y.
  • Journal Title: J Cell Biochem. Volume: 112 Pages: 147-156
  • Peer Reviewed
• [Journal Article] 【サイトカインと疾患 : あらたな病態モデルから治療へ】サイトカインシグナル伝達機構 JAK-STATの標準経路と非標準経路モデル (2010)
  • Author(s): 中嶋弘一, 小島裕正
  • Journal Title: 医学のあゆみ Volume: 234(5) Pages: 325-330
• [Journal Article] Laminin-511, inducer of hair growth, is down-regulated and its suppressor in hair growth, laminin-332 up-regulated in chemotherapy-induced alopecia (2010)
  • Author(s): Imanishi H, Tsuruta D, , Tateishi C, Sugawara K, Paus R, Tsuji T, Ishii M, Ikeda K, Kunimoto H, Nakajima K, Jones JC, Kobayashi H
  • Journal Title: J Dermatol Sci Volume: 58 Issue: 1 Pages: 43-54
  • DOI: 10.1016/j.jdermsci.2010.02.005
  • NAID: 10027400358
  • Peer Reviewed
• [Journal Article] GANP suppresses the arginine methyltransferase PRMT5 regulating IL-4-mediated STAT6-signaling to IgE production in B cells (2009)
  • Author(s): Igarashi H, Kuwahara K, Yoshida M, Xing Y, Maeda K, Nakajima K and Sakaguchi N
  • Journal Title: Mol Immunol Volume: 6 Issue: 6 Pages: 1031-41
  • DOI: 10.1016/j.molimm.2008.08.272
  • Peer Reviewed
• [Presentation] Phospho-Ser727 of STAT3 shortens the duration of STAT3 activity by enhancing the dephosphorylation of pY705 through nuclear TC45 (2011)
  • Author(s): Wakahara R, Kunimoto H, Kojima H, Nakajima K
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 千葉市
  • Year and Date: 2011-11-29
• [Presentation] Phospho-Ser727 of STAT3 shortens the duration of STAT3 activity by enhancing the dephosphorylation of pY705 through nuclear TC45 (2011)
  • Author(s): Wakahara R, Kunimoto H, Kojima H, Nakajima K
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉市)
  • Year and Date: 2011-11-29
• [Presentation] gp130-Stat3 signaling induces premature cellular senescence (2010)
  • Author(s): Kojima H, Kunimoto H, Nakajima K
  • Organizer: 第33回日本分子生物学会・第83回日本生化学会大会合同年会
  • Place of Presentation: 神戸市
  • Year and Date: 2010-12-10
• [Presentation] gp130-Stat3 signaling induces premature cellular senescence (2010)
  • Author(s): 小島裕正, 國本浩之, 中嶋弘一
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会 合同年会
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2010-12-10
• [Presentation] Prolonged stimulation of gp130 leads to premature senescence of human diploid fibroblasts (2010)
  • Author(s): Kojima H, Kunimoto H, Nakajima K
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-27
• [Presentation] Prolonged stimulation of gp130 leads to premature senescence of human diploid fibroblasts (2010)
  • Author(s): Kojima H, Kunimoto H, Nakajima K
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-27
• [Presentation] Prolonged stimulation of gp130 leads to premature senescence of human diploid fibroblasts (2009)
  • Author(s): Kojima H, Kunimoto H, Nakajima K
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜市
  • Year and Date: 2009-12-17
• [Presentation] Prolonged stimulation of gp130 leads to premature senescence of human diploid fibroblasts (2009)
  • Author(s): 小島裕正
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜 (神奈川)
  • Year and Date: 2009-12-17
• [Book] Tumor Dormancy and Cellular Quiescence and Senescence, Cancer, and Noncancer Pathologies : Interleukin-6 Induces Premature Senescence Involving the STAT3 and Insulin-Like Growth Factor-Binding Protein 5 (2013)
  • Author(s): Kojima H, Kunimoto H, Inoue T, Nakajima K.Aging
  • Publisher: (in press)
• [Remarks]
  • URL: http://www.med.osaka-cu.ac.jp/immune/.