インターロイキン6を初めとする種々のサイトカインは免疫系、血液系、あるいは炎症反応等の生体防御システムにおいて重要な役割を演じている生理活性物質である。さらにサイトカインは神経系、内分泌系、骨代謝、形態形成にも重要な役割を演じていることが明らかにされ、サイトカイン研究は現代医学や、生命科学に多大なる貢献をしてきた。しかしながら、1970年代においては、インターロイキン6を初めこれらのサイトカインの本態は全く不明であった。
1970年代末にBリンパ球に作用し、抗体産生細胞への分化を誘導するサイトカインに注目し、この分子の本態を明らかにすべく世界に先駆けて精製を試みることを開始した。1978年〜1980年にかけて、大阪府立羽曳野病院にて結核性胸膜炎患者胸水中のリンパ球は、Bリンパ球を抗体産生細胞に分化させる因子を多量に産生する事を発見した(論文1)。引き続き、熊本大学医学部 (1980〜1984年)にて、結核性胸膜炎胸水リンパ球培養上清より、等電点5.1で分子量2.2万のB細胞分化因子（TRF様因子/BCDF)、すなわちインターロイキン6(IL-6)の存在を発見し(論文2)、その精製を試みるとともに、作用機作の研究を続けた(論文3, 4)。
その後大阪大学細胞工学センターにてB細胞分化因子の精製を引き続け(論文5)、1986年にそのcDNAのクローニングに成功し、その全構造を決定した(論文6)。本因子は、世界中で3ケ所の研究グループがほぼ同時に全構造の決定に成功した結果、各々のグループが異なる名称を使用していたので、1988年にニューヨーク・アカデミーの主催する国際会議においてIL-6という名称に統一された。さらに心房内粘液腫の患者に観られる自己免疫様症状が、粘液腫を摘除することによって消失することに注目し、粘液腫が産生する何らかの因子が関与している可能性を考え、その因子の本態がIL-6であることを明らかにした(論文7)。また慢性関節リウマチ患者関節液中には、IL-6が著増していることを明らかにした(論文23)。さらに、形質細胞腫/多発性骨髄腫の増殖因子の本態がIL-6そのものであることを証明した(論文19)。これら一連の研究結果により、慢性炎症性増殖性疾患において、IL-6が病態を形成するのに重要な役割を演じていることを示唆すると共に、IL-6遺伝子の異常発現により慢性関節リウマチ等の自己免疫疾患や、形質細胞腫の発症が誘導される可能性を提唱した(総説論文19、22、27)。これら一連の研究をきっかけにして、IL-6のみならず、他のサイトカイン異常産生と、種々の疾患との関係が国際的に注目を浴びることになった。さらに、IL-6遺伝子異常発現によって自己免疫疾患や、形質細胞腫が実際に発症しうることを証明するために、ヒトIL-6遺伝子の異常発現を示すトランスジェニックマウスを作製した(論文52)。IL-6トランスジェニックマウスには、自己抗体産生を伴う、抗体産生細胞の著増を認めると共に、最終的に、移植可能な形質細胞腫が発症する事を証明した(論文87)。IL-6の作用機構を分子レベルで解明する目的で、IL-6の受容体をコードする遺伝子をクローニングし、その全構造を明らかにした(論文27、48、72)。
IL-6はBリンパ球の増殖分化のみならず、広く免疫応答、造血反応、炎症反応、及び神経系の細胞の増殖・分化、あるいは機能発現に重要な役割をしている多機能を有する典型的なサイトカインである(総説論文13、37、38)。しかしながら、サイトカインが、どのような分子機構で、このような多機能な生物活性を発揮しうるのかという点は全く不明であった。この点を明らかにすべく、大阪大学医学部バイオメディカル教育研究センターにおいて、IL-6受容体をモデルとしてサイトカイン受容体を介する細胞内シグナル伝達機構の研究を開始した。まず、IL-6シグナルの標的遺伝子としてjunB遺伝子を選びjunB遺伝子発現に必要なプロモーター領域を決定するとともにjunB遺伝子活性化に至るシグナル伝達経路にJAK-STAT伝達系が関与していることを証明した(論文93、99、105、総説論文34)。
IL-6は、骨髄性白血病細胞に作用し、増殖を抑制するとともに、マクロファージへの分化を誘導する(論文24)。一方、IL-6は多発性骨髄腫の強力な増殖因子である(論文19)。さらに、神経細胞に作用し、神経突起の伸長を誘導する(論文25)。単一のサイトカインであるIL-6がどのような機構で、このような異なる生物活性を発揮しうるのか? 又、これらの生物活性と、JAK-STATシグナル伝達系がどのように関与しているのか? このようなサイトカイン研究において、もっとも重要な疑問点を明らかにすべく、まずIL-6ファミリーのサイトカイン受容体の共通のシグナル伝達性サブユニットであるgp130の細胞内ドメインのどの領域が、各々増殖シグナル、増殖抑制シグナル、分化誘導シグナル、及び細胞の生存シグナルに必要であるかを明らかにした(論文106、107、110、119)。さらに、IL-6による骨髄性白血病細胞のマクロファージへの分化と、細胞増殖抑制には、STAT3の活性化が必須であることを発見した(論文107)。またgp130を介する細胞増殖シグナルには少なくとも3つ存在することを明らかにした。すなわちSTAT3の活性化を介する抗アポトーシスシグナルとG1-S移行シグナル、およびSHPｰ2/RAS/MAPKシグナルを介するS-G2/M移行シグナルである（論文110、119)。一方、神経突起の伸長シグナルにおいては、STAT3は逆に抑制的に作用することを明らかにした(論文113)。さらにこれらの研究を通じて、一つのサイトカイン受容体の異なる部分から同時に相反するシグナルが誘導されるという新しい事実を明らかにするとともに(論文107、113、119)、これらの相反するシグナルのバランスによって最終的なサイトカインの生物学的活性が決定されるのではないかというモデルを提唱し、サイトカインの機能多様性の分子機構の一端を説明できることを明らかにした(論文119、総説論文36)。
サイトカインの本態が全く不明であった1978年に大阪府立羽曳野病院で、結核性胸膜炎患者胸水リンパ球がB細胞分化因子を大量に産生していることを発見することによって始まった過去20年間におよぶ研究により、IL-6の発見と、その全構造の決定に成功したのみならず、慢性関節リウマチや多発性骨髄腫などの種々の病気にサイトカインが関与していることが明らかになった。さらに、サイトカインがどのような分子機構で、多機能な生物活性を発揮しうるのかという点が明らかになった（総説論文36、37、38)。現在大阪大学医学部バイオメディカル教育研究センター腫瘍病理学研究室では、生体内でインターロイキン６受容体を介するシグナル伝達経路が実際どのような生理活性に関与しているのかを明らかにするべく、シグナル特異的変異受容体を発現しているノックインマウスや各シグナル伝達分子を欠損しているノックアウトマウスを作成し免疫応答や、発生における役割を明らかにする努力を行っている。さらに神経系の初期発生や体軸形成の分子機構の解明や、これらの過程に関与するサイトカインやそのシグナル伝達経路の解明を明らかにすべく、ゼブラフィッシュやマウスを使用し、分子生物学的手法、発生工学的手法、遺伝学的手法をとりいれた新たな研究に挑戦しいる。すでにオーガナイザー形成と前頭部形成に必須の役割を果たしている新規なホメオボックス蛋白であるダルマを発見している（Genes & Development 12: 2345-2353, 1998）。このように多くの良き共同研究者とともになされたインターロイキン６をモデルとしたサイトカイン研究は、２０年という節目の年を迎えて新たなる研究へと展開しつつある。最近の研究内容に関しては研究室のホームページを参照していただければ幸いです。引き続きご鞭撻とご支援、ご指導のほどよろしくお願いいたします。
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*1) Hirano, T., T. Teranishi, H. Toba, N. Sakaguchi, T. Fukukawa, and I. Tsuyuguchi. Human helper T cell factor(s)(ThF). I. Partial purification and characterization. J. Immunol. 126:517-522, 1981.
*2) Teranishi, T., T. Hirano, N. Arima, and K. Onoue. Human helper Tcell factor(s)(ThF). II. Induction of IgG production in B lymphoblastoid cell lines and identification of T cell replacing factor-(TRF) like factor(s). J. Immunol. 128:1903-1908, 1982.
*3) Hirano, T., T. Teranishi, and K. Onoue. Human helper T cell factor(s). III. Characterization of B cell differentiation factor I(BCDF I). J. Immunol. 132:229-234, 1984.
*4) Hirano, T., T. Teranishi, Bi-Hu Lin, and K. Onoue. Human helper T cell factor(s). 1984. IV. Demonstration of human late- acting B cell differentiation factor acting on Staphylococcus aureus Cowan I-stimulated B cells. J. Immunol. 133:798-802, 1984.
*5) Hirano, T., T. Taga, N. Nakano, K. Yasukawa, S. Kashiwamura, K. Shimizu, K. Nakajima, K. H.Pyun, and T. Kishimoto. Purification to homogeneity and characterization of human B cell differentiation factor (BCDF or BSFp-2). Proc. Natl. Acad. Sci. USA. 82:5490-5494, 1985.
*6) Hirano, T., K. Yasukawa, H. Harada, T. Taga, Y. Watanabe, T. Matsuda, S. Kashiwamura, K. Nakajima, K. Koyama, A. Iwamatu, S. Tsunasawa, F. Sakiyama, H. Matsui, Y. Takahara, T. Taniguchi, and T. Kishimoto. Complementary DNA for a novel human inteleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. 324:73-76, 1986.
*7) Hirano, T., T. Taga, K. Yasukawa, K. Nakajima, N. Nakano, F. Takatsuki, M. Shimizu, A. Murashima, S. Tsunasawa, F. Sakiyama, and T. Kishimoto. Human B cell differentiation factor defined by an anti-peptide antibody and its possible role in autoantibody production. Proc. Natl. Acad. Sci. USA. 84:228-231, 1987.
8) Noma, T., T. Mizuta, A. Rosen, T. Hirano, T. Kishimoto, and T. Honjo. Enhancement of the interleukin 2 receptor expression on T cells by multiple B-lymphotropic lymphokines. Immunol. Lett. 15:249-253, 1987.
*9) Yasukawa, K., T. Hirano, Y. Watanabe, K. Muratani, T. Matsuda, and T. Kishimoto. Structure and expression of human B cell stimulatory factor 2 ( BSF-2/IL-6 ) gene. EMBO J. 6:2939-2945, 1987.
*10) Andus, T., T. Geiger, T. Hirano, H. Northoff, U, Ganter, J. Bauer, T. Kishimoto, and P. C. Heinrich. Recombinant human B cell stimulatory factor 2 (BSF-2/IFN b 2) regulates b-fibrinogen and albumin mRNA levels in Fao-9 cells. FEBS Lett. 221:18-22, 1987.
11) Taga, T., K. Kawanishi, R. R. Hardy, T. Hirano, and T. Kishimoto. Receptors for B cell stimulatory factor 2 ( BSF-2 ): Quantitation, Specificity, Distribution and Regulation of the Expression. J. Exp. Med. 166:967-981, 1987.
12) Hirano, T., T. Matsuda, K. Hosoi, A. Okano, H. Matsui, T. Kishimoto. Absence of antiviral activity in recombinant B cell stimulatory factor 2 ( BSF-2 ). Immunol. Lett. 17:41-45,1988.
*13) Muraguchi, A., T. Hirano, B. Tang, T. Matsuda, Y. Horii, K. Nakajima, and T. Kishimoto. The essential role of B cell stimulatory factor 2 ( BSF-2/IL-6 ) for the terminal differentiation of B cells. J. Exp. Med. 167:332-344,1988.
14) Tonouchi, N., N. Oouchi, N. Kashima, M. Kawai, K. Nagase, A. Okano, H. Matsui, K. Yamada, T. Hirano, and T. Kishimoto. High-level expression of human BSF-2/IL-6 cDNA in Escherichia coli using a new type of expression-preparation system. J. Biochem. 104:30-34, 1988.
15) Lotz, M., F. Jirik, R. Kabouridis, C. Tsoukas, T. Hirano, T. Kishimoto, and D. A. Carson. B cell stimulatory factor 2/Interleukin 6 is a costimulant for human thymocytes and T lymphocytes. J. Exp. Med. 167:1253-1258, 1988.
16) Reis, L. F. L., J. Le, T. Hirano, T. Kishimoto, and J.Vilcek. Antiviral action of tumor necrosis factor in human fibroblasts is not mediated by B cell-stimulatory factor 2(BSF2)/Interferon(IFN)-beta, and is inhibited by specific antibodies to IFN-beta. J. Immunol. 140:1566-1570,1988.
17) Andus, T., T. Geiger, T. Hirano, T. Kishimoto, T.-A. Tran-Thi, K. Decker and P. C. Heinrich. Regulation of synthesis and secretion of major rat acute-phase proteins by recombinant human interleuki-6 (BSF-2/IL-6) in hepatocyte primary cultures. Eur. J. Biochem. 173:287-293, 1988.
18) Castell, J. V., M. J. Gomez-Lechon, M. David, T. Hirano, T. Kishimoto, and P. C. Heinrich. Recombinant human interleukin-6 (IL-6/BSF-2/HSF) regulates the synthesis of acute phase proteins in human hepatocytes. FEBS Lett. 232:347-350, 1988.
*19) Kawano, M., T. Hirano, T. Matsuda, T. Taga, Y. Horii, K. Iwato, H. Asaoku, B. Tang, O. Tanabe, H. Tanaka, A. Kuramoto, and T. Kishimoto. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332:83-85, 1988.
20) Geiger, T., T. Andus, J. Klapproth, T. Hirano, T. Kishimoto, and P. C. Heinrich. Induction of rat acute-phase proteins by interleukin-6 in vivo. Eur. J. Immunol. 18:717-721, 1988.
21) Andus, T., T. Geiger, T. Hirano, T. Kishimoto, and P. C. Heinrich. Action of recombinant human interleukin 6, interleukin-1 and tumor necrosis factor alpha on the mRNA induction of acute-phase proteins. Eur. J. Immunol. 18:739-746, 1988.
*22) Matsuda, T., T. Hirano, and T. Kishimoto. Establishment of interleukin 6 (IL-6)/B cell stimulatory factor 2 (BSF-2)-dependent cell line and preparation of anti-IL-6/BSF-2 monoclonal antibodies. Eur. J. Immunol. 18:951-956, 1988.
*23) Hirano, T., T. Matsuda, M. Turner, K. Sato, G. Buchan, B. Tang, N. Miyasaka, M. Shimizu, R. Maini, M. Feldmann, and T. Kishimoto. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur. J. Immunol. 18:1797-1801, 1988.
*24) Miyaura, C., K. Onozaki, Y. Akiyama, T. Taniyama, T. Hirano, T. Kishimoto and T. Suda. Recombinant human interleukin 6 ( B-cell stimulatory factor 2 ) is a potent inducer of differentiation of mouse myeloid leukemia cells ( M1 ). FEBS Lett. 234:17-21, 1988.
*25) Sato, T., S. Nakamura, T. Taga, T. Matsuda, T. Hirano, T. Kishimoto, and Y. Kaziro. Induction of neural differentiation in PC12 cells by B cell stimulatory factor 2/interleukin 6. Mol. Cell. Biol. 8:3546-3549, 1988.
26) Asaoku, H., M. Kawano, K. Iwato, O. Tanabe, H. Tanaka, T. Hirano, T. Kishimoto, and A. Kuramoto. Decrease in BSF-2/IL-6 response in advanced cases of multiple myeloma. Blood 72:429-432, 1988.
*27) Yamasaki, K., T. Taga, Y. Hirata, H. Yawata, Y. Kawanishi, B. Seed, T. Taniguchi, T. Hirano, and T. Kishimoto. Cloning and expression of human interleukin 6 ( BSF-2/IFNb2 ) receptor. Science 241:825-828, 1988.
28) Castell, J. V., T. Geiger, V. Gross, T. Andus, E. Walter, T. Hirano, T. Kishimoto, and P. C. Heinrich. Plasma clerance, organ distribution and target cells of interleukin-6/hepatocyte stimulating factor in the rat. Eur. J. Biochem. 177: 357-361, 1988.
29) Horii, Y., A. Muraguchi, S. Suematsu, T. Matsuda, K. Yoshizaki, T. Hirano, and T. Kishimoto. Regulation of BSF-2/IL-6 production by human mononuclear cells: Macrophage-dependent synthesis of BSF-2/IL-6 by T cells. J. Immunol. 141:1529-1535,1988.
30) Okada, M., M. Kitahara, S. Kishimoto, T. Matsuda, T. Hirano,and T. Kishimoto. BSF-2/IL-6 functions as killer helper factor in the in vitro inducton of cytotoxic T cells. J. Immunol.141:1543-1549, 1988.
*31) Shimizu, S., T. Hirano, R. Yoshika, S. Sugai, T. Matsuda, T. Taga, T. Kishimoto, and S. Konda. Interleukin 6(B cell stimulatory factor 2)-dependent growth of a Lennert's lymphoma-derived T. cell line(KT-3). Blood 72:1826-1828, 1988.
32) Le, J., G. Fredrickson, L. F. L. Reis, T. Diamantstein, T. Hirano, T. Kishimoto, and J. Vilcek. Interleukin 2-dependent and interleukin 2-independent pathways of regulation of thymocyte function by interleukin 6. Proc. Natl. Acad. Sci. USA 85:8643-8647, 1988.
33) Takatsuki, F., A. Okano, C. Suzuki, R. Chieda, Y. Takahara, T. Hirano, T. Kishimoto, J. Hamuro, and Y. Akiyoma. Human recombinant interliukin 6/B cell stimulatory factor 2(IL-6/BSF-2) augments murine antigen-specific antibody responses in vitro and in vivo. J. Immunol. 141:3072-3077, 1988.
34) Tanabe, O., S. Akira, T. Kamiya, G. G. Wong, T. Hirano, and T. Kishimoto. Genomic structure of the murine IL-6 gene: High degree conservation of potential regulatory sequences between mouse and human. J. Immunol. 141:3875-3881, 1988.
35) Geiger, T., T. Andus, J. Bauer, H. Northoff, U. Ganter, T. Hirano, T. Kishimoto, and P. C. Heinrich. Cell-free synthesized interleukin-6(BSF-2/IFN- b 2) exhibits hepatocyte-stimulating activity. Eur. J. Biochem. 175:181-186, 1988.
36) Nakajima, K., O. Martinez-Maza, T. Hirano, P. G. Nishanian, J. Salazar-Gonzalez, J. L. Fahey, and T. Kihimoto. Induction of IL-6(BSF-2/IFN- b 2) production by the human immunodificiency virus(HIV). J. Immunol. 142:531-536, 1989.
37) Jirik, F. R., T. J. Podor, T. Hirano, T. Kishimoto, D. J. Loskutoff, D. A. Carson, and M. Lotz. Bacterial lipopolysaccharide and inflammatory mediators augment IL-6 secretion by human endotherial cells. J. Immunol. 142:144-147,1989.
38) Matsuda, T., T. Hirano, S. Nagasawa, and T. Kishimoto. Identificatioin of a2-macroglobulin as a carrier protein for interleukin 6. J. Immunol. 142:148-152, 1989.
39) Miyaura, C., C. H. Jin, Y. Yamaguchi, M. Tomida, M. Hozumi, T. Matsuda, T. Hirano, T. Kishimoto, and T. Suda. Production of interleukin 6 and its relation to macrophage differentiation of mouse myeloid leukemia cells (M1) treated with differentiation-inducing factor and 1a,25-dihydroxyvitamin D3. Biochem. Biophys. Res. Comm. 158:660-666, 1989.
40) Bereta, J., A. Kurdowska, A. Koji, T. Hirano, T. Kishimoto, J. Content, W. Fiers, P. B. Shegal, J. Van Damme and J. Gauldie. Different preparations of natural and recombinant human interleukin-6 (IFN- b 2, BSF-2) similarly stimulate acute phase protein synthesis and uptake of a-aminoisobutyric acid by cultured rat hepatocytes. Int. J. Biochem. 21:361-366, 1989.
41) Suzuki, C., A. Okano, F. Takatsuki, Y. Miyasaka, T. Hirano, T. Kishimoto, D. Ejima, and Y. Akiyama. Continuous perfusion with interleukin 6 (IL-6) enhances production of hematopoietic stem cells (CFU-S). Biochem. Biophys. Res. Comm. 159:933-938, 1989.
42) Miyasaka, N., K. Sato, J. Hashimoto, H. Kohsaka, K. Yamamoto, M. Goto, K. Inoue, Y. Matsuda, T. Hirano, T. Kishimoto, and K. Nishioka. Constitutive production of interleukin 6/B cell stimulatory factor-2 from inflammatory synovium. Clinical Immunology and Immunopathology 52:238-247, 1989.
43) Nishimoto, N., K. Yoshizaki, H. Tagoh, M. Monden, S. Kishimoto, T. Hirano, and T. Kishimoto. Elevation of serum interleukin 6 prior to acute phase proteins on the inflamation by surgical operation. Clinical Immunology and Immunopathology 50:399-401, 1989.
44) Okano, A., C. Suzuki, F. Takatsuki, Y. Akiyama, K. Koike, T. Nakahata, T. Hirano, T. Kishimoto, K. Ozawa, and S. Asano. Effects of interleukin-6 on hematopoiesis in bone marrow-transplanted mice. Transplantation 47:739-740, 1989.
*45) Beagley, K. W., J. H. Eldridge, F. Lee, H. Kiyono, M. P. Everson, W. J. Koopman, T. Hirano, T. Kishimoto, and J. R. Mcghee. Interleukins and IgA synthesis : Human and Murine interleukin 6 induce high rate IgA secretion in IgA-committed B cells. J. Exp. Med. 169:2133-2148, 1989.
46) Miki, S., M. Iwano. Y. Miki, M. Yamamoto. B. Tang, K. Yokokawa, T. Sonoda, T. Hirano, and T. Kishimoto. Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas. FEBS Letters 250:607-610, 1989.
47) Onozaki, K., Y. Akiyama, A. Okano, T. Hirano, T. Kishimoto, T. Hashimoto, K. Yoshizawa, and T. Taniyama. Synergistic regulatory effects of interleukin 6 and interleukin 1 on the growth and differentiation of human and mouse myeloid leukemic cell lines. Cancer Research 49:3602-3607, 1989.
*48) Taga, T., M. Hibi, Y. Hirata, K. Yamasaki, K. Yasukawa, T. Matsuda, T. Hirano, and T. Kishimoto. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 58:573-581, 1989.
49) Okano, A., C. Suzuki, F. Takatsuki, Y. Akiyama, K. Koike, K. Ozawa, T. Hirano, T. Kishimoto, T. Nakahata, and S. Asano. In vitro expansion of murine pluripotent hemopoietic stem cell population in response to IL-3 and IL-6. Application to bone marrow transplantation. Transplantation 48:495-498, 1989.
*50) Yoshizaki, K., T. Matsuda, N. Nishimoto, T. Kuritani, L. Taeho, K. Aozasa, T. Nakahata, H. Kawai, H. Tagoh, T. Komori, S. Kishimoto, T. Hirano, and T. Kishimoto. Pathological significance of interleukin 6 ( IL-6/BSF-2 ) in Castleman's disease. Blood, 74:1360-1367, 1989.
51) Ishibashi, T., H. Kimura, Y. Shikama, T. Uchida, S. Kariyone, T. Hirano, T. Kishimoto, F. Takatsuki, and Y. Akiyama. Interleukin-6 is a potent thrombopoietic factor in vivo in mice. Blood, 74:1241-1244, 1989.
*52) Suematsu, S., T. Matsuda, K. Aozasa, S. Akira, N. Nakano, S. Ohno, J. Miyazaki, K. Yamamura, T. Hirano, T. Kishimoto. IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc. Natl. Acad. Sci. USA. 86:7547-7551, 1989.
53) Raynal, M. C., Z. Liu, T. Hirano, L. Mayer, T. Kishimoto, and S. C. Kiang. Interleukin 6 induces secretion of IgG1 by coordinated transcriptional activation and differential mRNA accumulation. Proc. Natl. Acad. Sci. USA. 86:8024-8028, 1989.
54) Hirata, Y., T. Taga, M. Hibi, N. Nakano, T. Hirano, and T. Kishimoto. Characterization of IL-6 receptor expression by monoclonal and polyclonal antibodies. J. Immunol. 143:2900-2906, 1989.
55) Horii, Y., A. Muraguchi, M. Iwano, T. Matsuda, T. Hirayama, H. Yamada, Y. Fujii, K. Dohi, H. Ishikawa, Y. Ohmoto, K. Yoshizaki, T. Hirano, and T. Kishimoto. Involvement of interleukin-6 in mesangial proliferative glomerulonephritis. J. Immunol. 143:3949-3955, 1989.
56) Bauer, J., T. M. Bauer, T. Kalb, T. Taga, G. Lengyel, T. Hirano, T. Kishimoto, G. Acs, L. Mayer, and W. Gerok. Regulation of interleukin-6 receptor expression in human monocytes and monocyte-derived macrophages-comparison with the expression in human hepatocytes. J. Exp. Med. 170:1537-1549, 1989.
57) Breen, E. C., A. R. Rezai, K. Nakajima, G. N. Beall, R. T. Mitsuyasu, T. Hirano, T. Kishimoto, and O. Martinez-Maza. Infection with HIV is associated with elevated IL-6 levels and production. J. Immunol. 144:480-484, 1990.
58) Williams, N., T. Degiorgio, N. Banu, R. Withy, T. Hirano, T. Kishimoto. Recombinant interleukin-6 stimulates immature murine megakaryocytes. Exp. Hematol. 18:69-72, 1990.
59) Asano, S., A. Okano, K. Ozawa, T. Nakahata, T. Ishibashi, K. Koike, H. Kimura, Y. Tanioka, A. Shibuya, T. Hirano, T. Kishimoto, F. Takaku, and Y. Akiyama. In vivo Effects of recombinant human interleukin-6 in primates: stimulated production of platelets. Blood, 75:1602-1605, 1990.
60) Isshiki, H., S. Akira, O. Tanabe, T. Nakajima, T. Shimamoto, T. Hirano, and T. Kishimoto. Constitutive and IL-1 inducible factors interact with the IL-1 responsive element in the IL-6 gene. Mol. Cell. Biol. 10:2757-2764, 1990.
61) Akira, S., H. Isshiki, T. Sugita, O. Tanabe, S. Kinoshita, Y. Nishio, T. Nakajima, T. Hirano, and T. Kishimoto. A nuclear factor for IL-6 expression(NF-IL-6) is a member of a C/EBP family. EMBO J. 9:1897-1906, 1990.
62) Miles, S. A., A. R. Rezai, J. F. Salazar-Gonzalez, M. V. Meyden, R. H. Stevens, D. M. Logan, R. T. Mitsuyasu, T. Taga, T. Hirano, T. Kishimoto, and O. Martinez-Maza. AIDS Kaposi's sarcoma-derived cells produce and respond to interleukin 6. Proc. Natl. Acad. Sci. USA. 87:4068-4072, 1990.
63) Kr殳gen, A., S. Rose-John, C. M嗟er, B. Wroblowski,A. Wollmer, J. M殕berg, T. Hirano, T. Kishimoto and P. C. Heinrich. Structure-function analysis of human interleukin-6. Evidence for the involvement of the carboxy-terminus in function. FEBS Letters 262:323-326, 1990.
64) Takatsuki, F., A. Okano, C. Suzuki, Y. Miyasaka, T. Hirano, T. Kishimoto, D. Ejima and Y. Akiyama. Interleukin 6 perfusion stimulates reconstitution of the immune and hematopoietic systems after 5-fluorouracil treatment. Cancer Res. 50:2885-2890, 1990.
65) Sugita, T., T. Totsuka, M. Saito, K. Yamasaki, T. Taga, T. Hirano, and T. Kishimoto. Functional murine IL-6 receptor with the intracisternal A-particle gene product at its cytoplasmic domain: Its possible role in plasmacytomagenesis. J. Exp. Med. 171:2001-2009, 1990.
66) Rose-John, S., H. Schooltink, D. Lenz, E. Hipp, G. Dufhues, H. Schmitz, X. Schiel, T. Hirano, T. Kishimoto and P. C. Heinrich. Studies on the structure and regulation of the human hepatic interleukin-6 receptor. Eur. J. Biochem. 190: 79-83, 1990.
67) Kitahara, M., S. Kishimoto, T. Hirano, T. Kishimoto, and M. Okada. The in vivo anti-tumor effect of human recombinant IL-6. Jpn. J. Cancer Res. 81: 1032-1038, 1990.
68) Yasukawa, K., T. Saito, T. Fukunaga, Y. Sakimori, Y. Koishihara, H. Fukui, Y. Ohsugi, T. Matsuda, H. Yawata, T. Hirano, T. Taga and T. Kishimoto. Purification and Characterization of Soluble Human IL-6 Receptor Expressed in CHO Cells. J. Biochem. 108: 673-676, 1990.
69) Kameda, T., N. Matsuzaki, K. Sawai, T. Oakda, F. Saji, T. Matsuda, T. Hirano, T. Kishimoto, and O. Tanizawa. Production of interleukin-6 by normal human trophoblast. Placenta 11: 205-213, 1990.
70) Ishimi, Y., C. Miyaura, C. He Jin, T. Akatsu, Y. Nakamura, A. Yamaguchi, S. Yoshiki, T. Matsuda, T. Hirano, T. Kishimoto, and T. Suda. IL-6 is produced by osteoblasts and induces bone resorption. J. Immunol. 145: 3297-3303, 1990.
71) Yoshizaki, K., N. Nishimoto, K. Matsumoto, H. Tagoh, T. Taga, Y. Deguchi, T. Kuritani, T. Hirano, K. Hashimoto, N. Okada, and T. Kishimoto. Interleukin 6 and expression of its receptor on epidermal keratinocytes. Cytokine 2:381-387, 1990.
*72) Hibi, M., M. Murakami, M. Sito, T. Hirano, T. Taga and T. Kishimoto. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63:1149-1157, 1990.
73) Tang, B., T. Matsuda, S. Akira, N. Nagata, S. Ikehara, T. Hirano, and T. Kishimoto. Age-associated increase in interleukin-6 in MRL/lpr mice. Int. Immunol. 3:273-278, 1991.
74) Sugiyama, H., F. Wiener, M. Babonits, S. Silva, T. Hirano, T. Kishimoto and G. Klein. V-ABL does not abolish IL-6 requirement by murine plasmacytoma cells. Int. J. Cancer 48:234-238, 1991.
75) Fukatsu, A., S. Matsuo, H. Tamai, N. Sakamoto. T. Matsuda and T. Hirano. Distribution of interleukin 6 in normal and diseased human kidney. Lab. Invest. 65:61-66, 1991.
76) Lue, C., H. Kiyono, J. R. McGhee, K. Fujihashi, T. Kishimoto, T. Hirano, and J. Mestecky. Recombinant human interleukin 6(rhIL-6) promotes the terminal differentiation of in vivo-activated human B cells into antibody- secreting cells. Cell. Immunol. 132:423-432, 1991.
77) Dohi, K., M. Iwano, A. Muraguchi, Y. Horii, T. Hirayama, S. Ogawa, H. Shiki, T. Hirano, T. Kishimoto and H. Ishikawa. The prognostic significance of urinary interleukin 6 in IgA nephropathy. Clinical Nephrology 35:1-5, 1991.
78) Kono, Y., K. W. Beagley, K. Fujihashi, T. Taga, T. Hirano, T. Kishimoto, J. R. McGhee, and H. Kiyono. Cytokine regulation of lecalized inflammation: induction of activated B cells and IL-6-mediated polyclonal IgG and IgA synthesis in inflamed human gingiva. J. Immunol. 146:1812-1821, 1991.
79) Rose-John, S., E. Hipp, D. Lenz, L. G. Legr, H. Korr, T. Hirano, T. Kishimoto, and P. C. Heinrich. Structural and functional studies on the human interleukin-6 receptor. J. Biol. Chem. 266:3842-3846, 1991.
80) Fujihashi, K., J. R. McGhee, C. Lue, K. W. Beagley, T. Taga, T. Hirano, T. Kishimoto, J. Mestecky, and H. Kiyono. Human appendix B cells Naturally express receptors for and respond to interleukin 6 with selective IgA1 and IgA2 synthesis. J. Clin. Invest. 88:248-252, 1991.
81) Fukunaga, M., Y. Fujiwara, M. Fujibayashi, S. Ochi, K. Yokoyama, A. Ando, T. Hirano, N. Ueda and T. Kamada. Signal transduction mechanism of interleukin 6 in cultured rat mesangial cells. FEBS Letters 285:265-267, 1991.
82) Sidell, N., T. Taga, T. Hirano, T. Kishimoto and A. Saxon. Retinoic acid-induced growth inhibition of a human myeloma cell line via down-reguration of IL-6 receptors. J. Immunol. 146:3809-3814, 1991.
83) Schooltink, H., T. Stoyan, D. Lenz, H. Schmitz, T. Hirano, T. Kishimoto, P. C. Heinrich and S. Rose-John. Structural and functional studies on the human hepatic interleukin 6 receptor. Biochem. J. 277:659-664, 1991.
84) Saito, T., K. Yasukawa, H. Suzuki, K. Futatsugi, T. Fukunaga, C. Yokomizo, Y. Koishihara, H. Fukui, Y. Ohsugi, H. Yawata, T. Hirano, T. Taga, and T. Kishimoto. Preparation of soluble murine IL-6 receptor and anti-murine IL-6 receptor antibodies. J. Immunol. 147:168-173, 1991.
85) Ohta, Y., I. Katayama, T. Funato, H. Yokozeki, T. Hirano, T. Kishimoto, and K. Nishioka. In situ expression of Messenger RNA of interleukin-1 and interleukin-6 in psoriasis: interleukin-6 involved in formation of psoriatic lesions. Arch Dermatol Res 283:351-356, 1991.
86) Takenawa, J., Y. Kaneko, M. Fukumoto, A. Fukatsu, T. Hirano, H. Fukuyama, H. Nakayama, J. Fujita, and O. Yoshida. Enhanced expression of interleukin-6 in primary human renal cell carcinomas. J. Nat. Cancer Inst. 83:1668-1672, 1991.
*87) Suematsu, S., T. Matsusaka, T. Matsuda, S. Ohno, J. Miyazaki, K. Yamamura, T. Hirano, and T. Kishimoto. Generation of transplantable plasmacytomas with t(12;15) in IL-6 transgenic mice. Proc. Natl. Acad. Sci. USA 89:232-235, 1992.
88) Nakajima, T., S. Yamamoto, M. Cheng, K. Yasukawa, T. Hirano, T. Kishimoto, T. Tokunaga and M. Honda. Soluble interleukin-6 receptor is released from receptor-bearing cell lines in vitro. Jpn. J. Cancer Res. 83: 373-378, 1992.
89) Kasukabe, T., J. Okabe-Kado, Y. Honma, N. Hozumi, T. Matsuda and T. Hirano. Characterization of growth inhibitory factors for mouse monocytic leukemia cells. Leukemia Research 16: 139-144, 1992.
90) Oritani, K., T. Kaisho, K. Nakajima and T. Hirano. Retinoic acid inhibits interleukin 6-induced macrophage differentiation and apoptosis in a murine hematopoietic cell line, Y6. Blood 80: 2298-2305, 1992.
91) Kobayashi, I., T. Matsuda, T. Saito, K. Yasukawa, H. Kikutani, T. Hirano, T. Taga and T. Kishimoto. Abnormal distrubution of IL-6 receptor in aged MRL/Ipr mice: elevanted expression on B cells and absence on CD4+ cells. Int. Immunol. 4: 1407-1412, 1992.
92) Ishibashi, T., Y. Shikama, H. Kimura, M. Kawaguchi, T. Uchida, T. Yamamoto, A. Okano, Y. Akiyama, T. Hirano, T. Kishimoto and Y. Maruyama. Thrombopoietic effects of interleukin-6 in long-term administration in mice. Exp. Hematol. 21: 640-646, 1993.
*93) Nakajima, K., T. Kusafuka, T. Takeda, Y. Fujitani, K. Nakae and T. Hirano. Identification of a novel interleukin 6 responsive element containing an Ets-binding site and a CRE-like site in the junB promoter. Mol. Cell. Biol. 13: 3027-3041, 1993.
*94) Muraoka, O., T. Kaisho, M. Tanabe, and T. Hirano. Transcriptional activation of the interleukin 6 gene by HTLV-1 p40tax through an NF-kB-like binding site. Immunol. Letters, 37: 159-165, 1993.
95) Iwano, M., K. Dohi, E. Hirata, N. Kurumatani, Y. Horii, H. Shiiki, A. Fukatsu,T. Matsuda, T. Hirano, T. Kishimoto and H. Ishikawa. Urinary levels of IL-6 in patients with active lupus nephritis. Clin. Nephrology 40: 16-21, 1993.
96) Matsuda, T., Y. Yamanaka, and T. Hirano. Interleukin-6-induced tyrosine phosphorylation of multiple proteins in murine hematopoietic lineage cells. Biochem. Biophys. Res. Comm. 200: 821-828, 1994.
97) Matsuda, T., and T. Hirano. Association of p72 tyrosine kinase with Stat factors and its activation by IL-3, IL-6 and G-CSF. Blood 83: 3457-3461, 1994.
98) Matsuda, T., and T. Hirano. Establishment of the ELISA for murine soluble gp130, a signal transducer for the IL-6 family cytokine and its detection in the ascitic fluids of tumor-bearing mice. Biochem. Biophys. Res. Comm. 202: 637-642, 1994.
99) Fujitani, Y., K. Nakajima, H. Kojima, K. Nakae, T. Takeda, and T. Hirano. Transcriptional activation of the IL-6 response element in the junB promoter is mediated by multiple stat family proteins. Biochem. Biophys. Res. Comm. 202: 1181-1187, 1994.
*100) Takeda, T., K. Nakajima, H. Kojima and T. Hirano. E1A repression of IL-6-induced gene activation by blocking the assembly of IL-6 response element binding complexes. J. Immunol. 153: 4573-4582, 1994.
101) Matsuda, T., M. Takahashi-Tezuka, T. Fukada, Y. Okuyama, Y. Fujitani, S. Tsukada, H. Mano, H. Hirai, O.N. Witte, and T. Hirano. Association and activation of Btk and Tec tyrosine kinases by gp130, a signal transducer of the IL-6 family of cytokines. Blood, 85: 627-633,1995.
102) Matsuda, T., T. Fukada, M. Takahashi-Tezuka, Y. Okuyama, Y. Fujitani, Y. Hanazono, H. Hirai, and T. Hirano. Activation of Fes tyrosine kinase by gp130, an Interleukin-6 family cytokine signal transducer, and their association. J. Biol. Chem. 270:11037-11039, 1995.
103) Nakae, K., K. Nakajima, J. Inazawa, T. Kitaoka, and T. Hirano. ERM, a PEA3 subfamily of Ets transcription factors, can cooperate with c-Jun. J. Biol. Chem. 270: 23795-23800, 1995.
104) Sanc斬u, J., T. Kaisho, T. Hirano, and J. Wietzerbin. Triggering of the human interleukin-6 gene by interferon-g and tumor necrosis factor-a in monocytic cells involves cooperation between Interferon Regulatory Factor-1, NFkB, and Sp1 transcription factors. J. Biol. Chem. 270: 27920-27931, 1995.
105) Kojima, H., K. Nakajima, and T. Hirano. IL-6-inducible complexes on an IL-6 response element of the junB promoter contain Stat3 and 36 kDa CRE-like site binding protein(s). Oncogene 12: 547-554, 1996.
*106) Yamanaka, Y., K. Nakajima, T. Fukada, M. Hibi, and T. Hirano. Differentiation and growth arrest signals generate through the cytoplasmic region of gp130 that is essential for Stat3 activation. EMBO J. 15:1557-1565, 1996.
*107) Nakajima, K., Y. Yamanaka, K. Nakae, H. Kojima, N. Kiuchi, M. Ichiba, T. Kitaoka, T. Fukada, M. Hibi and T. Hirano. A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. EMBO J. 15:3651-3658, 1996.
108) Sekimoto, T., K. Nakajima, T. Tachibana, T. Hirano and Y. Yoneda. Interferon-g-dependent nuclear import of stat1 is mediated by the GTPase activity of Ran/TC4. J. Biol. Chemistry 241:31017-31020, 1996.
*109) Moffatt, S., N. Tanaka, K. Tada, M. Nose, M. Nakamura, O. Muraoka, T. Hirano, and K. Sugamura. A cytotoxic non-structural protein, NS1, of human parvovirus B19 induces activation of interleukin 6 (IL-6) gene expression. J. Virol. 70:8485-8491.
*110) Fukada, T., M. Hibi, Y. Yamanaka, M. Takahashi-Tezuka, Y. Fujitani, T. Yamaguchi, K. Nakajima, and T. Hirano. Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 5: 449-460, 1996.
*111) Fujitani, Y., M. Hibi, T. Fukada, M. Takahashi-Tezuka, H. Yoshida, T. Yamaguchi, K. Sugiyama, Y. Yamanaka, K. Nakajima, and T. Hirano. An alternative pathway for STAT activation that is mediated by the direct interaction between JAK and STAT. Oncogene 14:751-761, 1997.
112) Takahashi-Tezuka, M., M. Hibi, Y. Fujitani, T. Fukada, T. Yamaguchi, and T. Hirano. Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK. Oncogene 14: 2273-2282, 1997.
*113) Ihara, S., K. Nakajima, T. Fukada, M. Hibi, S. Nagata, T. Hirano, and Y. Fukui. Dual control of neurite outgrowth by STAT3 and MAP kinase in PC12 cells stimulated with interleukin-6. EMBO J. 17: 5345-5352, 1997
114) Shimozaki, K., K. Nakajima, T. Hirano, and S. Nagata. Involvement of STAT3 in the granulocyte colony stimulating factor-induced differentiation of myeloid cells. J. Biol. Chem. 272: 25184-25189, 1997.
115) Sekimoto, T., N. Imamoto, K. Nakajima, T. Hirano, and Y. Yoneda. Extracellular signal-dependent nuclear import of stat1 is mediated by nuclear pore-targeting complex formation with (Via) NPI-1, not Rch1. EMBO J. 16: 7067-7077, 1997.
116) Narimatsu, M., K. Nakajima, M. Ichiba, M., and T. Hirano. Association of Stat3-dependent transcriptional activation of p19INK4D with the IL-6-induced growth arrest. Biochem. Biophys. Res. Comm. 238: 764-768, 1997.
117) Ichiba, M., K. Nakajima, Y. Yamanaka, N. Kiuchi and T. Hirano Autoregulation of the Stat3 gene through cooperation with a CRE site binding protein. J. Biol. Chem. 273:6132-6138, 1998
*118) Takahashi-Tezuka*, M., Y. Yoshida*, T. Fukada, T. Yamaguchi, Y. Yamanaka, K. Nakajima, M. Hibi, and T. Hirano. Gab1 acts as an adaptor molecule linking a cytokine receptor gp130 to ERK MAP kinase. Mol. Cell. Biol. 18:4109-4117, 1998. (equal contribution of the first two authors*)
*119) Fukada, T., T. Ohtani, Y. Yoshida, T. Shirogane, K. Nishida, K. Nakajima, M. Hibi, and T. Hirano. STAT3 orchestrates contradictory signals in cytokine-induced G1 to S cell cycle transition. EMBO J, in press
120) Kiuchi, N., K. Nakajima, M. Ichiba, T. Fukada, M. Narimatsu, K. Mizuno, M. Hibi, and T. Hirano. STAT3 is required for the gp130-mediated full activation of the c-myc gene. J. Exp. Med. in press, 1999.
1) Kishimoto, T. and T. Hirano. Molecular regulation of B lymphocyte response. Ann. Rev. Immunol. 6:485-512, 1988.
2) Kishimoto, T., and T. Hirano Pleiotropic functions of B cell stimulatory factor 2 ( BSF-2/IL-6 ). BioEssays, 9:11-15,1988.
3) Hirano, T. and T. Kishimoto. Interleukin-6 (IL-6):possible implications in human diseases. Research in Clinic and Laboratory, 19, 1-10, 1989.
4) Hirano, T., and T. Kishimoto. Chapter 4-6-4: Interleukin 6. Human Monocyte, edited by G. L. Asherson and M. Zembala, Academic Press, pp217-226, 1989.
5) Kishimoto, T. and T. Hirano. Chapter 14: B lymphocyte activation, proliferation and immunoglobulin secretion. Fundamental Immunology, second edition., editied by W. E. Paul, Raven Press, pp385-411, 1989.
6) Hirano, T., T. Taga, K. Yamasaki, T. Matsuda, B. Tang, A. Muraguchi, Y. Horii, S. Suematsu, Y. Hirata, H. Yawata, M. Shimizu, M. Kawano, and T. Kishimoto. A multifunctional cytokine, IL-6/BSF-2 and its receptor. Int. Arch. Allergy Appl. Immunol. 88:29-33, 1989.
7) Hirano, T., T. Taga, K. Yamasaki, T. Matsuda, B. Tang, S. Suematsu, Y. Horii, Y. Hirata, H. Yawata, A. Muraguchi, M. Kawano, M. Shimizu, and T. Kishimoto. Interleukin 6 and its receptor: Pathological role in autoimmunity and lymphoid malignancy. Advances in Immunopharmacology 4:161-168, 1989.
8) Hirano, T., T. Taga, K. Yamasaki, T. Matsuda, Y. Hirata, H. Yawata, O. Tanabe, S. Akira, and T. Kishimoto. Molecular cloning of the cDNAs for interleukin-6/B cell stimulatory factor-2 and its receptor. Annals of New York Academy of Sciences, 557:167-180, 1989.
9) Matsuda, T., S. Suematsu, M. Kawano, K. Yoshizaki, B. Tang, O. Tanabe, T. Hirano, and T. Kishimoto. IL-6/BSF2 in nomal and abnormal regulation of immune responses. Annals of New York Academy of Sciences, 557:466-477, 1989.
10) Hirano, T., and T. Kishimoto. Interleukin 6 and plasma cell neoplasias. Progress in Growth Factor Research, edt. by J. K. Health, Pergamon press, Oxford, 1:133-142, 1989.
11) Kishimoto, T., T. Taga, T. Matsuda, M. Hibi, S. Suematsu, B. Tang, H. Yawata, Y. Hirata, K. Yamasaki, and T. Hirano. Interleukin 6 and its receptor in immune regulation. Progress in Immunology, VII: 633-640, 1989.
12) Taga, T., M. Hibi, Y. Hirata, H. Yawata, S. Natsuka, K. Yasukawa, T. Totsuka, K. Yamasaki, T. Hirano, and T. Kishimoto. Interleukin-6 receptor and a unique mechanism of its signal transduction. Cold Spring Harbor Symposia on Quantitative Biology 54:713-721, 1989.
*13) Hirano, T., and T. Kishimoto. Chapter 14: Interleukin 6. In Handbook of Experimental Pharmacology vol. 95/I "Peptide Growth Factors and Their Receptors" edited by M. B. Sporn and A. B. Roberts, Springer-Verlag, pp633-665, 1990.
14) Hirano, T., T. Taga, T. Matsuda, M. Hibi, S. Suematsu, B. Tang, M. Murakami, and T. Kishimoto. Interleukin 6 and its receptor in the immune response and hematopoiesis. Int. J. Cell Cloning 8:155-167, 1990.
15) Akira, S., T. Hirano, T. Taga, and T. Kishimoto. The biology of multifunctional cytokines; IL-6 and related molecules (IL-1 and TNF) FASEB J. 4: 2860-2867, 1990.
16) Hirano, T. Chapter 28: Interleukin 6 in immune response and Hematopoiesis. In Hematological Growth Factors in Clinical Applications (edited by R. Mertelsmann and F. Herrmann). Marcel Dekker, Inc. New York pp471-488, 1990.
17) Matsuda, T., and T. Hirano. Interleukin 6 ( IL-6). Biotherapy 2: 363-373, 1990.
18) Hirano, T., S. Akira, T. Taga, and T. Kishimoto. Biological and clinical aspects of interleukin 6. Immunology Today, 11: 443-449, 1990.
*19) Hirano, T. Interleukin 6 (IL-6) and its receptor: Their role in plasma cell neoplasias. Int. J. Cell Cloning 9: 166-184, 1991.
20) Hirano, T. Interleukin 6(IL-6). Chapeter 8, The Cytokine Handbook, edited by A. Thomson, Academic Press, pp169-190, 1991.
21) Hirano, T., and T. Kishimoto. Interleukin 6 and autoimmune diseases. Molecular Autoimmunity, edited by N. Talal, Academic press. pp177-194, 1991.
22) Hirano, T. Interleukin-6 and its relation to inflammation and disease. Clinical Immunol. Immunopathol. 62:S60-S65, 1992.
23) Hirano, T. The biology of interleukin 6. Chemical Immunol. 51:153-180, 1992.
24) Hirano, T., S. Suematsu, T. Matsusaka, T. Matsuda and T. Kishimoto. The role of interleukin 6 in plasmacytomagenesis. in Polyfunctional cytokines : IL-6 and LIF, Ciba Foundation Symposium 167:188-196, 1992.
25) Hirano, T. Role of interleukin 6 in autoimmunity and plasma cell neoplasias. in Concise Reviews in Clinical and Experimental Hematology, edited by M. J. Murphy, Jr. AlphaMed Press, Dayton, pp189-201, 1992.
26) Hirano, T. IL-6 and B cell abnormalities: An overview and future prospects. in IL-6: Physiopathology and Clinical Potentials, edited by M. Revel, Raven Press, Vol. 88, pp85-95, 1992.
*27) Hirano, T. Interleukin 6 and autoimmunity and plasma cell neoplasias. Res. Immunol. 143: 759-763, 1992.
28) Hirano, T., and T. Kishimoto. Chapter 16. Interleukins 4, 5 and 6. Clinical Aspects of Immunology 5th edition, edited P. J. Lachmann, Sir K. Peters, by F. S. Rosen Blackwell Scientific Publications LTD, Oxford pp299-313, 1993.
29) Matsuda, T., T. Nakajima, T. Kaisho, K. Nakajima and T. Hirano. Interleukin 6 receptor and signal transduction. Advances in Cell and Molecular Biology of Membranes and Organelles. 3: 65-92, 1994.
30) Nakajima, K., T. Takeda, Y. Fujitani, K. Nakae, H. Kojima and T. Hirano. Interleukin 6 receptor-mediated signal transduction pathways. Gann Monograph on Cancer Research 42: 37-49, 1994.
31) Hirano, T. Chapter 8, Interleukin 6. The Cytokine Handbook, 2nd edition, edited by A. W. Thomson, Academic Press, pp145-168, 1994.
32) Hirano, T. Interleukin 6 transgenic mouse: A model of chronic inflammatory proliferative disease. Overexpression and knockout of cytokines in transgenic mice. edited by C. O. Jacob. Academic Press pp73-84, 1994.
33) Hirano, T., T. Matsuda, and K. Nakajima. Signal transduction through gp130 that is shared among the receptors for the interleukin 6 related cytokine subfamily. Stem Cells, 12: 262-277, 1994.
*34) Nakajima, K., T. Matsuda, Y. Fujitani, H. Kojima, Y. Yamanaka, K. Nakae, T. Takeda and T. Hirano. Signal transduction through IL-6 receptor: involvement of multiple protein kinases, Stat factors and a novel H-7-sensitive pathway. Ann. New York Acad. Sci. 762: 55-70, 1995.
35) Hibi, M., Nakajima, K., Hirano, T. IL-6 cytokine family and signal transduction: a model of the cytokine system. J. Mol. Med. 74:1-12, 1996.
*36) Hirano, T., K. Nakajima, and M. Hibi. Signaling mechanisms through gp130: a model of the cytokine system. Cytokine & Growth Factor Reviews, 8: 241-252, 1997
*37) Hirano, T. Interleukin 6 and its receptor: Ten years later. Intern. Rev. Immunol., 16:249-284, 1998
*38) Hirano, T. Interleukin 6. The Cytokine Handbook, 3rd edition, edited by A. W. Thomson, Academic Press, pp197-228, 1998.
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