Abstract
In the late 1960s, the essential role of T-cells in antibody production was reported. This suggested to us that certain molecules should be released from T-cells for the stimulation of B-cells. We discovered activities in the culture supernatant of T-cells that induced proliferation and differentiation of B-cells. The factor that induced B-cells to produce immunoglobulins was named B-cell stimulatory factor (BSF)-2. The complementary DNA that encoded human BSF-2 was cloned in 1986. Simultaneously, interferon-β2 and 26-kDa protein in the fibroblasts were independently cloned by different groups and were found to be identical to BSF-2. Later, a hybridoma/plasmacytoma growth factor and a hepatocyte-stimulating factor also were proven to be the same molecule as BSF-2. Various names were used for this molecule because of its multiple biological activities, and thereafter, these names were unified as interleukin (IL)-6. Since the discovery of IL-6, rapid progress has been made in understanding its actions, the IL-6 receptor system, and the IL-6 signal transduction mechanism. More importantly, it was involved in numerous diseases, such as rheumatoid arthritis and Castleman’s disease. By accumulating the basic knowledge, a new therapeutic approach by blocking IL-6 actions appeared to be feasible for chronic inflammatory diseases.
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Miller, J. F. and Mitchell, G. F. (1968), J. Exp. Med. 128, 801–820.
Claman, H. N., Chaperon, E. A., and Selner, J. C. (1968), Proc. Soc. Exp. Biol. Med. 127, 462–466.
Kishimoto, T. and Ishizaka, K. (1973), J. Immunol. 111, 1194–1205.
Kishimoto, T. and Ishizaka, K. (1973), J. Immunol. 111, 720–732.
Kishimoto, T. and Ishizaka, K. (1973), J. Immunol. 111, 1–9.
Schimpl, A. and Wecker, E. (1973), Adv. Exp. Med. Biol. 29, 179–182.
Kishimoto, T., Miyake, T., Nishizawa, Y., Watanabe, T., and Yamamura, Y. (1975), J. Immunol. 115, 1179–1184.
Parker, D. C., Wadsworth, D. C., and Schneider, G. B. (1980), J. Exp. Med. 152, 138–150.
Hirano, T., Kuritani, T., Kishimoto, T., and Yamamura, Y. (1977), J. Immunol. 119, 1235–1241.
Yoshizaki, K., Nakagawa, T., Kaieda, T., Muraguchi, A., Yamamura, Y., and Kishimoto T. (1982), J. Immunol. 128, 1296–1301.
Kishimoto, T., Hirano, T., Kuritani, T., Yamamura, Y., Ralph, P., and Good, R. A. (1978), Nature 271, 756–758.
Howard, M., Farrar, J., Hilfiker, M., et al. (1982), J. Exp. Med. 155, 914–923.
Noma, Y., Sideras, P., Naito, T., et al. (1986), Nature 319, 640–646.
Takatsu, K., Tominaga, A., and Hamaoka, T. (1980), J. Immunol. 124, 2414–2422.
Swain, S. L. and Dutton, R. W. (1982), J. Exp. Med. 156, 1821–1834.
Kinashi, T., Harada, N., Severinson, E., et al. (1986), Nature 324, 70–73.
Hirano, T., Yasukawa, K., Harada, H., et al. (1986), Nature 324, 73–76.
Hirano, T., Matsuda, T., Hosoi, K., Okano, A., Matsui, H., and Kishimoto, T. (1988), Immunol. Lett. 17, 41–45.
Potter, M. and Boyce, C. R. (1962), Nature 193, 1086,1087.
Nordan, R. P., Pumphrey, J. G., and Rudikoff, S. (1987), J. Immunol. 139, 813–817.
Suematsu, S., Matsusaka, T., Matsuda, T., et al. (1992), Proc. Natl. Acad. Sci. USA 89, 232–235.
Kawano, M., Hirano, T., Matsuda, T., et al. (1988), Nature 332, 83–85.
Gauldie, J., Richards, C., Harnish, D., Lansdorp, P., and Baumann, H. (1987), Proc. Natl. Acad. Sci. USA 84, 7251–7255.
Andus, T., Geiger, T., Hirano, T., et al. (1987), FEBS Lett. 221, 18–22.
Kopf, M., Baumann, H., Freer, G., et al. (1994), Nature 368, 339–342.
Noma, T., Mizuta, T., Rosen, A., Hirano, T., Kishimoto, T., and Honjo T. (1987), Immunol. Lett. 15, 249–253.
Okada, M., Kitahara, M., Kishimoto, S., Matsuda, T., Hirano, T., and Kishimoto, T. (1988), J. Immunol. 141, 1543–1549.
Le, J., Fredrickson, G., Reis, L., et al. (1988), Proc. Natl. Acad. Sci. USA 85, 8643–8647.
Lotz, M., Jirik, F., Kabouridis, R., et al. (1988), J. Exp. Med. 167, 1253–1258.
Ceuppens, J. L., Baroja, M. L., Lorre, K., Van Damme, J., and Billiau, A. (1988), J. Immunol. 141, 3868–3874.
Garman, R. D., Jacobs, K. A., Clark, S. C., and Raulet, D. H. (1987), Proc. Natl. Acad. Sci. USA 84, 7629–7633.
Leary, A., Ikebuchi, K., Hirai, Y., et al. (1988), Blood 71, 1759–1763.
Ikebuchi, K., Wong, G. G., Clark, S. C., Ihle, J. N., Hirai, Y., and Ogawa, M. (1987), Proc. Natl. Acad. Sci. USA 84, 9035–9039.
Stanley, E. R., Bartocci, A., Patinkin, D., Rosendaal, M., and Bradley, T. R. (1986), Cell 45, 667–674.
Koike, K., Nakahata, T., Takagi, M., et al. (1988), J. Exp. Med. 168, 879–890.
Ogawa, M. (1993), Blood 81, 2844–2853.
Nicola, N. A., Metcalf, D., Matsumoto, M., and Johnson, G. R. (1983), J. Biol. Chem. 258, 9017–9023.
Ishibashi, T., Kimura, H., Uchida, T., Kariyone, S., Friese, P., and Burstein, S. A. (1987), Proc. Natl. Acad. Sci. USA 86, 5953–5957.
Ishibashi, T., Kimura, H., Shikama, Y., et al. (1989), Blood 74, 1241–1244.
Koike, K., Nakahata, T., Kubo, T., et al. (1990), Blood 75, 2286–2291.
Yamasaki, K., Taga, T., Hirata, Y., et al. (1988), Science 241, 825–828.
Seed, B. and Aruffo, A. (1987), Proc. Natl. Acad. Sci. USA 84, 3365–3369.
Taga, T., Hibi, M., Hirata, Y., et al. (1989), Cell 58, 573–581.
Hibi, M., Murakami, M., Saito, M., Hirano, T., Taga, T., and Kishimoto, T. (1990), Cell 63, 1149–1157.
Ip, N. Y., Nye, S. H., Boulton, T. G., et al. (1992), Cell 69, 1121–1132.
Gearing, D. P., Comeau, M. R., Friend, D. J., et al. (1992), Science 255, 1434–1437.
Liu, J., Modrell, B., Aruffo, A., et al. (1992), J. Biol. Chem. 267, 16,763–16,766.
Yin, T., Taga, T., Tsang, M. L., Yasukawa, K., Kishimoto, T., and Yang, Y. C. (1993), J. Immunol. 151, 2555–2561.
Pennica, D., Shaw, K. J., Swanson, T. A., et al. (1995), J. Biol. Chem. 270, 10,915–10,922.
Akira, S., Isshiki, H., Sugita, T., et al. (1990), EMBO J. 9, 1897–1906.
Isshiki, H., Akira, S., Sugita, T., et al. (1991), N. Biol. 3, 63–70.
Nakajima, T., Kinoshita, S., Sasagawa, T., et al. (1993), Proc. Natl. Acad. Sci. USA 90, 2207–2211.
Darnell, J. E., Kerr, I. M., and Stark, G. M. (1994), Science 257, 803–806.
Ihle, J. N., Witthuhn, B. A., Quelle, F. W., et al. (1994), Trends Biochem. Sci. 19, 222–227.
Schindler, C. and Darnell, J. E. Jr. (1995), Annu. Rev. Biochem. 64, 621–651.
Murakami, M., Narazaki, M., Hibi, M., et al. (1991), Proc. Natl. Acad. Sci. USA 88, 11,349–11,353.
Murakami, M., Hibi, M., Nakagawa, N., et al. (1993), Science 260, 1808–1810.
Silvennoinen, O., Witthuhn, B. A., Quelle, F. W., Cleveland, J. L., Yi, T., and Ihle, J. N. (1993), Proc. Natl. Acad. Sci. USA 90, 8429–8433.
Watling, D., Guschin, D., Muller, M., et al. (1993), Nature 366, 166–170.
Silvennoinen, O., Ihle, J. N., Schlessinger, J., and Levy, D. E. (1993), Nature 366, 583–585.
Wegenka, U. M., Buschmann, J., Lutticken, C., Heinrich, P. C., and Horn, F. (1993), Mol. Cell Biol. 13, 276–288.
Akira, S., Nishio, Y., Inoue, M., et al. (1994), Cell 77, 63–71.
Zhong, Z., Wen, Z., and Darnell, J. E. Jr. (1994), Science 264, 95–98.
Guschin, D., Rogers, N., Briscoe, J., et al. (1995), EMBO J. 14, 1421–1429.
Naka, T., Narazaki, M., Hirata, M., et al. (1997), Nature 387, 924–929.
Starr, R., Willson, T. A., Viney, E. M., et al. (1997), Nature 387, 917–921.
Endo, T. A., Masuhara, M., Yokouchi, M., et al. (1997), Nature 387, 921–924.
Masuhara, M., Sakamoto, H., Matsumoto, A., et al. (1997), Biochem. Biophys. Res. Comm. 239, 436–446.
Minamoto, S., Ikegame, K., Ueno, K., et al. (1997), Biochem. Biophys. Res. Comm. 237, 79–83.
Hilton, D. J., Richardson, R. T., Alexander, W. S., et al. (1998), Proc. Natl. Acad. Sci. USA 95, 114–119.
Schmitz, J., Weissenbach, M., Haan, S., Heinrich, P. C., and Schaper, F. (2000), J. Biol. Chem. 275, 12,848–12,856.
Nicholson, S. E., Willson, T. A., Farley, A., et al. (1999), EMBO J. 18, 375–385.
Chung, C. D., Liao, J., Lui, B., et al. (1997), Science 278, 1803–1805.
Liu, B., Liao, J., Rao, X., et al. (1998), Proc. Natl. Acad. Sci. USA 95, 10,626–10,631.
Hirano, T., Taga, T., Nakano, N., et al. (1985), Proc. Natl. Acad. Sci. USA 82, 5490–5494.
Jourdan, M., Bataille, R., Seguin, J., Zhang, X. G., Chaptal, P. A., and Klein, B. (1990), Arthritis Rheum. 33, 398–402.
Hirano, T., Matsuda, T., Turner, M., et al. (1988), Eur. J. Immunol. 18, 1797–1801.
Yoshizaki, K., Matsuda, T., Nishimoto, N., et al. (1989), Blood 74, 1360–1367.
Sato, K., Tsuchiya, M., Saldanha, J., et al. (1993), Cancer Res. 53, 851–856.
Nishimoto, N., Sasai, M., Shima, Y., et al. (2000), Blood 95, 56–61.
Ohshima, S., Saeki, Y., Mima, T., et al. (1998), Proc. Natl. Acad. Sci. USA 95, 8222–8226.
Sasai, M., Saeki, Y., Ohshima, S., et al. (1999), Arthritis Rheum. 42, 1635–1643.
Hata, T., Sakaguchi, N., Yoshitomi, H., et al. (2004), J. Clin. Invest. 114, 582–588.
Nishimoto, N., Yoshizaki, K., Miyasaka, N., et al. (2004), Arthritis Rheum. 50, 1761–1769.
Yokota, S., Miyamae, T., Imagawa, T., et al. (2005), Arthritis Rheum. 52, 818–825.
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Kishimoto, T. IL-6. Clinic Rev Allerg Immunol 28, 177–185 (2005). https://doi.org/10.1385/CRIAI:28:3:177
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DOI: https://doi.org/10.1385/CRIAI:28:3:177