CURRICULUM VITAE

Japanese

CURRICULUM VITAE

Name:

Toshio Hirano

Birth Place:

Osaka, Japan

Birth Date:

April 17, 1947

Sex:

Male

Married Status:

Married, two children

Nationality:

Japanese

Present Position:

Professor, Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences and Department of Molecular Oncology, Graduate School of Medicine, Osaka University

Mailing address

Department of Molecular Oncology (C7), Graduate School of Medicine, Osaka University, 2-2, Yamada-oka Suita, Osaka 565-0871, Japan

TEL

81-6-6879-3880

FAX

81-6-6879-3889

Academic Record:

graduated Osaka University Medical School,1972.

passed the 53th National Board Examination for Medical License,1972.

Degree:

Medical Doctor, Osaka University, 1972.

PhD ( Doctor of Medical Science ),Osaka University, 1979.

Appointment:

Post-doctoral fellow, the 3rd Dept. of Internal Medicine, Osaka Univ. Medical School ( Professor Y. Yamamura ), from April, 1972 to June, 1973.

Visiting fellow, Gerontology Research Center, National Institute on Aging, National Institutes of Health, USA( Dr. T. Makinodan and Dr. A. A. Nordin ),from June, 1973 to June, 1976

Research fellow, the 3rd Dept. of Internal Medicine, Osaka Univ. Medical School( Professor Y. Yamamura ),from June, 1976 to Sept., 1978.

Medical staff, Dept. of Internal Medicine, Osaka Prefectural Habikino Hospital, from Oct., 1978 to April, 1980.

Associate Professor, Dept. of Biochemistry,Institute for Medical Immunology, Kumamoto University Medical School,(Professor K. Onoue) from May, 1980 to January, 1984.

Associate Professor, Division of Immunology, Institute for Molecular and Cellular Biology, Osaka University.(Professor T. Kishimoto), from January, 1984 to October, 1989.

Professor, Division of Molecular Oncology, Department of Oncology, Biomedical Research Center, Osaka University Medical School. from November, 1989 to 2001

Director, Biomedical Research Center, Osaka University Medical School, from October, 1997 to 1999.

Professor, Department of Molecular Oncology, Graduate School of Medicine, Osaka University from April, 2001-to present time

Group Director, RIKEN Research Center for Allergy and Immunology (RCAI), from Sept., 2001-to present time

Professor, Department of Frontier Biosciences, Graduate School of Frontier Biosciences, Osaka University, from April, 2002-to present time

Dean, Graduate School of Frontier Biosciences, Osaka University, from April 2004-March 2006

Prize:

Erwin von Balz prize (Japan), 1986

CIBA-GEIGY Rheumatism Prize (Japan), 1990

THE SANDOZ PRIZE FOR IMMUNOLOGY (now known as the Novartis Prizes for Immunology ), 1992

Osaka Science Prize (Japan), 1997

Mochida Memorial Prize (Japan), 1998

ISI Citation Laureate Award (Japan), 1981-98, 2000

The Fujihara Prize, 2004 The Fujihara Foundation of Science

Medical Award of The Japan Medical Association, 2005, The Japan Medical Association

The Emperor's Purple Ribbon Medal, April, 2006

Professional Activities:

Member of the Japanese Society for Immunology

Member of the Japanese Society for Cancer

Member of the Japanese Society of Molecular Biology

Member of the Japanese Biochemical Society

Member of the Japanese Society of Hematology

Member of the American Association of Immunologists

President of the Japanese Society for Immunology (2005-2006)

Board Member of the Japanese Society for Immunology (1987 to present time)

Member of the director board of the Japanese Society for Immunology (1992-1994, 1997-2000, 2003-2006)

Council Member of the International Society of Immunopharmacology(1991-　　)

Member of the editorial board of Cytokine (1989- )

Member of the Associate Editors of the J. Molecular Medicine (1994- )

Board Member of the Japanese Society for Cancer (1995- )

Member of the editorial board of International Immunopharmacology (1995- )

Summary of Research Achievements

The immune system plays a pivotal role in the defense reaction against infectious microorganisms. A variety of cytokines, such as interleukin 6(IL-6) are critically involved in the regulation of the growth and differentiation of lymphocytes in the immune system. Furthermore, cytokines are involved in hematopoiesis, nervous system, endocrine system and bone metabolism which are important to maintain the homeostasis.

We found that pleural effusion cells of the patients with tuberculous pleurisy produce a large amount of soluble factors capable of inducing immunoglobulin production in B lymphocytes in Osaka Prefectural Habikino Hospital in the late 1970 (J. Immunol. 126:517-522, 1981). Furthermore, we found that the same culture supernatant of the pleural effusion cells contains an active factor having the same biological activity and physicochemical properties of a cytokine, which is now called IL-6 (J. Immunol. 128:1903-1908, 1982). We continued purification and characterization of IL-6 in Kumamoto University (J. Immunol. 132:229-234, 1984, J. Immunol. 133:798-802, 1984.) and finally succeeded on the molecular cloning of human IL-6 in Osaka University in 1986 (Nature 324:73-76, 1986). Since then, it has been shown that IL-6 is a multifunctional cytokine acting in the immune response, acute phase response, nervous system, endocrine system and bone metabolisms. Furthermore, we found that a large amount of IL-6 is present in the synovial fluids of patients with rheumatoid arthritis (RA), first suggesting the involvement of IL-6 in RA (Eur. J. Immunol. 18:1797-1801, 1988) and IL-6 is a growth factor of myeloma (Nature 332:83-85, 1988.) (see reviews Immunology Today, 11, 443-449, 1990, Intern. Rev. Immunol., 16:249-284, 1998 ). To understand the molecular mechanisms of IL-6 action, we cloned IL-6 receptor alpha chain and gp130 (Science 241:825-828, 1988., Cell 58:573-581, 1989, Cell 63:1149-1157, 1990.). Furthermore, we established IL-6 induces two major signal transduction pathways, the Stat3 signal and the SHP2/Gab/MAPK signal in a manner dependent on the YxxQ motief and the Y759 of gp130, respectively (EMBO J. 15:1557, 1996, EMBO J. 15, 3651-3658, 1996, Immunity, 5:449, 1996, EMBO J, 16, 6670-6677, 1998, Mol. Cell Biol18, 4109-4117, 1998, Immunity, 11, 709-719, 1999, Blood, 93, 1806-1816, 1999, see reviews, Cytokine Growth Factor Reviews, 8, 241-252, 1997 and Oncogene, 19: 2548, 2000). In order to clarify the in vivo roles of each of the two signals of gp130, we generated a series of knock-in mouse lines in which the gp130-mediated SHP2 or Stat3 signal is selectively disrupted (Immunity, 12, 95, 2000). To make the SHP2 signal-deficient mice (gp130F759/F759), we mutated Y759 of gp130 to phenylalanine (F759) . The results indicate that the Y759-dependent signals negatively regulate the biological responses elicited by the Stat3-mediated signals in vivo. The most intriguing finding is that the gp130F759/F759 mice develop RA-like joint disease accompanied by autoantibody production and accumulated memory/activated T cells (J. Exp Med. 196: 979, 2002). This is the first definitive evidence showing that IL-6 is critically involved in spontaneous autoimmune disease and showed that abnormal cytokine signal can induce autoimmune disease like RA. Hirano is actually one of discoverers of IL-6 and during the last 25 years, he and his colleagues have very much contributed to clarification of the molecular mechanisms of IL-6 action in vitro and in vivo. Based on a large amount of a series of studies, we finally showed the disturbance of IL-6 signal is actually involved in the process of RA-like disease.

The regulation of cell movement plays critical roles in early embryonic development and the immune responses. It is suggested that gp130/JAK/STAT3 signal regulates cell movement. Spemann's organizer can specify the fate of the surrounding tissue and initiate highly integrated cell movements during gastrulation. Although the cell movement that occurs during gastrulation is well understood, little is known of the molecular mechanisms that initiate and coordinate this process. We showed that mouse and zebrafish STAT3 is required for the correct morphogenetic movements during gastrulation (Dev. Cell. 2: 363-375, 2002). To clarify the molecular mechanisms by which gp130/JAK/STAT3 signal transduction pathway regulates cell movement, we have recently identified a membrane protein as one of target genes of Stat3 and showed the identified gene product is critically invovled in cell movement of zebrafish gastrulation (manuscript in preparation).

These studies on IL-6 and its signal transduciton pathways have provided the molecular basis for the cytokine system in general. Furthermore, these have greatly contributed to the understanding of the molecular mechanisms of a variety of chronic inflammatory proliferative diseases and cancers.

Partial Publication List

Original Papers (Partial list, 30 out of 209)

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) 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.

9) 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

10) 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

11) 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

12) 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

13) 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.

14) 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.

15) 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.

16) 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, 1996

17) 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

18) 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, 1996

19) 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. 16: 5345-5352, 1997

20) 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, 16, 6670-6677, 1998

21) 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 Biol18, 4109-4117, 1998

22) Yamanaka, Y., T. Mizuno, Y. Sasai, M. Kishi, H. Takeda, C.-H. Kim, M. Hibi and T. Hirano. A novel homeobox gene, dharma, can induce the organizer in a non-cell-autonomous manner. Genes & Development, 12: 2345-2353, 1998.

23) 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. 189: 63-73, 1999

24) Shirogane, T., T. Fukada, J.M.M. Muller, D. T. Shima, M. Hibi, and T. Hirano, Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and anti-apoptosis. Immunity, 11, 709-719, 1999

25) Nishida, K., Y. Yoshida, M. Itoh, T. Fukada, T. Ohtani, T. Shirogane, T. Atsumi, M. Takahashi-Tezuka, K. Ishihara, M. Hibi, and T. Hirano. Gab-family adapter proteins act downstream of cytokine and growth factor receptors, and T and B cell antigen receptors. Blood, 93, 1806-1816, 1999

26) Itoh, M., Yoshida, Y., Nishida, K., Narimatsu, M., Hibi, M., and Hirano, T. A role of Gab1 for heart, placenta, and skin development, and growth factors- and cytokines-induced ERK MAP kinase activation. Mol. Cell. Biol. 20, 3695-3704, 2000.

27) Ohtani, T., K. Ishihara, T. Atsumi, K. Nishida, Y. Kaneko, T. Miyata�, S. Itoh, M. Narimatsu, H. Maeda, T. Fukada､, M. Itoh, H. Okano, M. Hibi and T. Hirano. Dissection of signaling cascades through gp130 in vivo: Reciprocal roles for STAT3- and SHP2-mediated signals in immune responses.Immunity, 12, 95-105, 2000

28) Yamashita, S., C. Miyagi, A. Carmany-Rampey, T. Shimizu, R. Fujii, A. F. Schier and T. Hirano. Stat3 controls cell movements during zebrafish gastrulation. Dev. Cell. 2: 363-375, 2002

29) Nishida, K*., L. Wang, E*., Mori, S.-J. Park, M. Narimatsu, S. Itoh, S. Yamasaki, M. Fujishima, K. Ishihara, M. Hibi, Y. Kitamura, and T. Hirano (*equal contribution). Requirement of Gab2 for mast cell development and Kitl/c-Kit signaling. Blood. 99:1866-1869, 2002.

30) Atsumi, T*., K. Ishihara*, D. Kamimura, H. Ikushima, T. Ohtani, S. Hirota, H. Kobayashi, S-.J. Park, Y. Saeki, Y. Kitamura, and T. Hirano. (*equal contribution). A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis. J. Exp Med. 196: 979, 2002

Reviews (partial list, 10 out of 76)

1) 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.

2) Hirano, T., S. Akira, T. Taga, and T. Kishimoto. Biological and clinical aspects of interleukin 6. Immunology Today, 11, 443-449, 1990

3) Hirano, T. Interleukin 6(IL-6). Chapeter 8, The Cytokine Handbook, edited by A. Thomson, Academic Press, pp169-190, 1991.

4) 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.

5) 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 , (Full Text)

6) Hirano, T. Interleukin 6. The Cytokine Handbook, 3rd edition, edited by A. W. Thomson, Academic Press, pp197-228, 1998.

7) Hirano, T. Interleukin 6 and its receptor: Ten years later. Intern. Rev. Immunol., 16:249-284, 1998, (Full Text)

8) Hirano, T., K. Ishihara, M. Hibi. Roles of STAT3 in mediating the cell growth, differentiation, and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene, 19: 2548, 2000

9) Hirano, T., and Fukada, T. IL-6 ligand and receptor family. Cytokine Reference, edited by Oppenheim, J. J., Feldmann, M., Durum, S. K., Hirano, T., Vilcek, J., Nicola, N.A. Academic Press. Vol. 1, pp523-535. 2001.

10) Hirano, T. Cytokines in autoimmune disease and chronic inflammatory proliferative disease. edited by Hirano, T. Editorial for Cytokine Growth Factor Rev, 13：297-298, 2002. (PubMed)

Publication list

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Publication list

Name:	Toshio Hirano
Birth Place:	Osaka, Japan
Birth Date:	April 17, 1947
Sex:	Male
Married Status:	Married, two children
Nationality:	Japanese
Present Position:	Professor, Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences and Department of Molecular Oncology, Graduate School of Medicine, Osaka University
Mailing address	Department of Molecular Oncology (C7), Graduate School of Medicine, Osaka University, 2-2, Yamada-oka Suita, Osaka 565-0871, Japan
TEL	81-6-6879-3880
FAX	81-6-6879-3889
Academic Record:	graduated Osaka University Medical School,1972.
Academic Record:	passed the 53th National Board Examination for Medical License,1972.
Degree:	Medical Doctor, Osaka University, 1972.
Degree:	PhD ( Doctor of Medical Science ),Osaka University, 1979.
Appointment:	Post-doctoral fellow, the 3rd Dept. of Internal Medicine, Osaka Univ. Medical School ( Professor Y. Yamamura ), from April, 1972 to June, 1973.
	Visiting fellow, Gerontology Research Center, National Institute on Aging, National Institutes of Health, USA( Dr. T. Makinodan and Dr. A. A. Nordin ),from June, 1973 to June, 1976
	Research fellow, the 3rd Dept. of Internal Medicine, Osaka Univ. Medical School( Professor Y. Yamamura ),from June, 1976 to Sept., 1978.
	Medical staff, Dept. of Internal Medicine, Osaka Prefectural Habikino Hospital, from Oct., 1978 to April, 1980.
	Associate Professor, Dept. of Biochemistry,Institute for Medical Immunology, Kumamoto University Medical School,(Professor K. Onoue) from May, 1980 to January, 1984.
	Associate Professor, Division of Immunology, Institute for Molecular and Cellular Biology, Osaka University.(Professor T. Kishimoto), from January, 1984 to October, 1989.
	Professor, Division of Molecular Oncology, Department of Oncology, Biomedical Research Center, Osaka University Medical School. from November, 1989 to 2001
	Director, Biomedical Research Center, Osaka University Medical School, from October, 1997 to 1999.
	Professor, Department of Molecular Oncology, Graduate School of Medicine, Osaka University from April, 2001-to present time
	Group Director, RIKEN Research Center for Allergy and Immunology (RCAI), from Sept., 2001-to present time
	Professor, Department of Frontier Biosciences, Graduate School of Frontier Biosciences, Osaka University, from April, 2002-to present time
	Dean, Graduate School of Frontier Biosciences, Osaka University, from April 2004-March 2006


Prize:	Erwin von Balz prize (Japan), 1986
	CIBA-GEIGY Rheumatism Prize (Japan), 1990
	THE SANDOZ PRIZE FOR IMMUNOLOGY (now known as the Novartis Prizes for Immunology ), 1992
	Osaka Science Prize (Japan), 1997
	Mochida Memorial Prize (Japan), 1998
	ISI Citation Laureate Award (Japan), 1981-98, 2000
	The Fujihara Prize, 2004 The Fujihara Foundation of Science
	Medical Award of The Japan Medical Association, 2005, The Japan Medical Association
	The Emperor's Purple Ribbon Medal, April, 2006


Professional Activities:	Member of the Japanese Society for Immunology
	Member of the Japanese Society for Cancer
	Member of the Japanese Society of Molecular Biology
	Member of the Japanese Biochemical Society
	Member of the Japanese Society of Hematology
	Member of the American Association of Immunologists

	President of the Japanese Society for Immunology (2005-2006)
	Board Member of the Japanese Society for Immunology (1987 to present time)
	Member of the director board of the Japanese Society for Immunology (1992-1994, 1997-2000, 2003-2006)
	Council Member of the International Society of Immunopharmacology(1991-　　)
	Member of the editorial board of Cytokine (1989- )
	Member of the Associate Editors of the J. Molecular Medicine (1994- )
	Board Member of the Japanese Society for Cancer (1995- )
	Member of the editorial board of International Immunopharmacology (1995- )

Summary of Research Achievements	The immune system plays a pivotal role in the defense reaction against infectious microorganisms. A variety of cytokines, such as interleukin 6(IL-6) are critically involved in the regulation of the growth and differentiation of lymphocytes in the immune system. Furthermore, cytokines are involved in hematopoiesis, nervous system, endocrine system and bone metabolism which are important to maintain the homeostasis. We found that pleural effusion cells of the patients with tuberculous pleurisy produce a large amount of soluble factors capable of inducing immunoglobulin production in B lymphocytes in Osaka Prefectural Habikino Hospital in the late 1970 (J. Immunol. 126:517-522, 1981). Furthermore, we found that the same culture supernatant of the pleural effusion cells contains an active factor having the same biological activity and physicochemical properties of a cytokine, which is now called IL-6 (J. Immunol. 128:1903-1908, 1982). We continued purification and characterization of IL-6 in Kumamoto University (J. Immunol. 132:229-234, 1984, J. Immunol. 133:798-802, 1984.) and finally succeeded on the molecular cloning of human IL-6 in Osaka University in 1986 (Nature 324:73-76, 1986). Since then, it has been shown that IL-6 is a multifunctional cytokine acting in the immune response, acute phase response, nervous system, endocrine system and bone metabolisms. Furthermore, we found that a large amount of IL-6 is present in the synovial fluids of patients with rheumatoid arthritis (RA), first suggesting the involvement of IL-6 in RA (Eur. J. Immunol. 18:1797-1801, 1988) and IL-6 is a growth factor of myeloma (Nature 332:83-85, 1988.) (see reviews Immunology Today, 11, 443-449, 1990, Intern. Rev. Immunol., 16:249-284, 1998 ). To understand the molecular mechanisms of IL-6 action, we cloned IL-6 receptor alpha chain and gp130 (Science 241:825-828, 1988., Cell 58:573-581, 1989, Cell 63:1149-1157, 1990.). Furthermore, we established IL-6 induces two major signal transduction pathways, the Stat3 signal and the SHP2/Gab/MAPK signal in a manner dependent on the YxxQ motief and the Y759 of gp130, respectively (EMBO J. 15:1557, 1996, EMBO J. 15, 3651-3658, 1996, Immunity, 5:449, 1996, EMBO J, 16, 6670-6677, 1998, Mol. Cell Biol18, 4109-4117, 1998, Immunity, 11, 709-719, 1999, Blood, 93, 1806-1816, 1999, see reviews, Cytokine Growth Factor Reviews, 8, 241-252, 1997 and Oncogene, 19: 2548, 2000). In order to clarify the in vivo roles of each of the two signals of gp130, we generated a series of knock-in mouse lines in which the gp130-mediated SHP2 or Stat3 signal is selectively disrupted (Immunity, 12, 95, 2000). To make the SHP2 signal-deficient mice (gp130F759/F759), we mutated Y759 of gp130 to phenylalanine (F759) . The results indicate that the Y759-dependent signals negatively regulate the biological responses elicited by the Stat3-mediated signals in vivo. The most intriguing finding is that the gp130F759/F759 mice develop RA-like joint disease accompanied by autoantibody production and accumulated memory/activated T cells (J. Exp Med. 196: 979, 2002). This is the first definitive evidence showing that IL-6 is critically involved in spontaneous autoimmune disease and showed that abnormal cytokine signal can induce autoimmune disease like RA. Hirano is actually one of discoverers of IL-6 and during the last 25 years, he and his colleagues have very much contributed to clarification of the molecular mechanisms of IL-6 action in vitro and in vivo. Based on a large amount of a series of studies, we finally showed the disturbance of IL-6 signal is actually involved in the process of RA-like disease. The regulation of cell movement plays critical roles in early embryonic development and the immune responses. It is suggested that gp130/JAK/STAT3 signal regulates cell movement. Spemann's organizer can specify the fate of the surrounding tissue and initiate highly integrated cell movements during gastrulation. Although the cell movement that occurs during gastrulation is well understood, little is known of the molecular mechanisms that initiate and coordinate this process. We showed that mouse and zebrafish STAT3 is required for the correct morphogenetic movements during gastrulation (Dev. Cell. 2: 363-375, 2002). To clarify the molecular mechanisms by which gp130/JAK/STAT3 signal transduction pathway regulates cell movement, we have recently identified a membrane protein as one of target genes of Stat3 and showed the identified gene product is critically invovled in cell movement of zebrafish gastrulation (manuscript in preparation). These studies on IL-6 and its signal transduciton pathways have provided the molecular basis for the cytokine system in general. Furthermore, these have greatly contributed to the understanding of the molecular mechanisms of a variety of chronic inflammatory proliferative diseases and cancers.
Partial Publication List	Original Papers (Partial list, 30 out of 209) 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) 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. 9) 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 10) 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 11) 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 12) 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 13) 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. 14) 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. 15) 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. 16) 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, 1996 17) 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 18) 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, 1996 19) 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. 16: 5345-5352, 1997 20) 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, 16, 6670-6677, 1998 21) 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 Biol18, 4109-4117, 1998 22) Yamanaka, Y., T. Mizuno, Y. Sasai, M. Kishi, H. Takeda, C.-H. Kim, M. Hibi and T. Hirano. A novel homeobox gene, dharma, can induce the organizer in a non-cell-autonomous manner. Genes & Development, 12: 2345-2353, 1998. 23) 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. 189: 63-73, 1999 24) Shirogane, T., T. Fukada, J.M.M. Muller, D. T. Shima, M. Hibi, and T. Hirano, Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and anti-apoptosis. Immunity, 11, 709-719, 1999 25) Nishida, K., Y. Yoshida, M. Itoh, T. Fukada, T. Ohtani, T. Shirogane, T. Atsumi, M. Takahashi-Tezuka, K. Ishihara, M. Hibi, and T. Hirano. Gab-family adapter proteins act downstream of cytokine and growth factor receptors, and T and B cell antigen receptors. Blood, 93, 1806-1816, 1999 26) Itoh, M., Yoshida, Y., Nishida, K., Narimatsu, M., Hibi, M., and Hirano, T. A role of Gab1 for heart, placenta, and skin development, and growth factors- and cytokines-induced ERK MAP kinase activation. Mol. Cell. Biol. 20, 3695-3704, 2000. 27) Ohtani, T., K. Ishihara, T. Atsumi, K. Nishida, Y. Kaneko, T. Miyata�, S. Itoh, M. Narimatsu, H. Maeda, T. Fukada､, M. Itoh, H. Okano, M. Hibi and T. Hirano. Dissection of signaling cascades through gp130 in vivo: Reciprocal roles for STAT3- and SHP2-mediated signals in immune responses.Immunity, 12, 95-105, 2000 28) Yamashita, S., C. Miyagi, A. Carmany-Rampey, T. Shimizu, R. Fujii, A. F. Schier and T. Hirano. Stat3 controls cell movements during zebrafish gastrulation. Dev. Cell. 2: 363-375, 2002 29) Nishida, K., L. Wang, E., Mori, S.-J. Park, M. Narimatsu, S. Itoh, S. Yamasaki, M. Fujishima, K. Ishihara, M. Hibi, Y. Kitamura, and T. Hirano (equal contribution). Requirement of Gab2 for mast cell development and Kitl/c-Kit signaling. Blood. 99:1866-1869, 2002. 30) Atsumi, T., K. Ishihara, D. Kamimura, H. Ikushima, T. Ohtani, S. Hirota, H. Kobayashi, S-.J. Park, Y. Saeki, Y. Kitamura, and T. Hirano. (equal contribution). A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis. J. Exp Med. 196: 979, 2002 Reviews (partial list, 10 out of 76) 1) 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. 2) Hirano, T., S. Akira, T. Taga, and T. Kishimoto. Biological and clinical aspects of interleukin 6. Immunology Today, 11, 443-449, 1990 3) Hirano, T. Interleukin 6(IL-6). Chapeter 8, The Cytokine Handbook, edited by A. Thomson, Academic Press, pp169-190, 1991. 4) 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. 5) 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 , (Full Text) 6) Hirano, T. Interleukin 6. The Cytokine Handbook, 3rd edition, edited by A. W. Thomson, Academic Press, pp197-228, 1998. 7) Hirano, T. Interleukin 6 and its receptor: Ten years later. Intern. Rev. Immunol., 16:249-284, 1998, (Full Text) 8) Hirano, T., K. Ishihara, M. Hibi. Roles of STAT3 in mediating the cell growth, differentiation, and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene, 19: 2548, 2000 9) Hirano, T., and Fukada, T. IL-6 ligand and receptor family. Cytokine Reference, edited by Oppenheim, J. J., Feldmann, M., Durum, S. K., Hirano, T., Vilcek, J., Nicola, N.A. Academic Press. Vol. 1, pp523-535. 2001. 10) Hirano, T. Cytokines in autoimmune disease and chronic inflammatory proliferative disease. edited by Hirano, T. Editorial for Cytokine Growth Factor Rev, 13：297-298, 2002. (PubMed)
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