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Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir.

Hirano T - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2010)

Bottom Line: Characterization of IL-6 revealed a multifunctional cytokine that is involved in not only immune responses but also hematopoiesis, inflammation, and bone metabolism.F759 arthritis is dependent on CD4(+) T cells, IL-6, and IL-17A, and is enhanced by the pX gene product from human T cell leukemia virus 1 (HTLV-1).Furthermore, this interaction is mediated by the IL-6 amplifier through STAT3 and NF-kappaB.

View Article: PubMed Central - PubMed

Affiliation: JST-CREST, WPI Immunology Frontier Research Center, Osaka University, Japan. hirano@molonc.med.osaka-u.ac.jp

ABSTRACT
In this review, the author discusses the research that led to the identification and characterization of interleukin 6 (IL-6), including his own experience isolating IL-6, and the roles this cytokine has on autoimmune and inflammatory diseases. The cDNAs encoding B-cell stimulatory factor 2 (BSF-2), interferon (IFN)-beta2 and a 26-kDa protein were independently cloned in 1986, which in turn led to the identification of each. To resolve the confusing nomenclature, these identical molecules were named IL-6. Characterization of IL-6 revealed a multifunctional cytokine that is involved in not only immune responses but also hematopoiesis, inflammation, and bone metabolism. Moreover, IL-6 makes significant contributions to such autoimmune and inflammatory diseases as rheumatoid arthritis (RA).IL-6 activates both the STAT3 and SHP2/Gab/MAPK signaling pathways via the gp130 signal transducer. F759 mice, which contain a single amino-acid substitution in gp130 (Y759F) and show enhanced STAT3 activation, spontaneously develop a RA-like arthritis as they age. F759 arthritis is dependent on CD4(+) T cells, IL-6, and IL-17A, and is enhanced by the pX gene product from human T cell leukemia virus 1 (HTLV-1). Arthritis development in these mice requires that the F759 mutation is present in nonhematopoietic cells, but not in immune cells, highlighting the important role of the interaction between nonimmune tissues and the immune system in this disease. Furthermore, this interaction is mediated by the IL-6 amplifier through STAT3 and NF-kappaB. Ultimately, this model may represent a general etiologic process underlying other autoimmune and inflammatory diseases. More importantly, the understanding of IL-6 has paved the way for new therapeutic approaches for RA and other autoimmune and inflammatory diseases.

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Related in: MedlinePlus

IL-6 receptor is composed of two subunits: an IL-6–specific alpha chain subunit and the signal transducer gp130.
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fig04: IL-6 receptor is composed of two subunits: an IL-6–specific alpha chain subunit and the signal transducer gp130.

Mentions: After IL-6 was cloned, we isolated its receptor in the late 1980s. In fact, we cloned a cDNA encoding the IL-6 receptor using expression cloning, which had just been introduced by Brian Seed and his colleagues.62) Then, we cloned the signal-transducing receptor subunit gp130,63,64) demonstrating that the IL-6 receptor comprises an IL-6–specific alpha chain subunit and the gp130 signal transducer (Fig. 4). Interestingly, gp130 functions not only as a receptor subunit for IL-6, but also as a signal transducer for other cytokines, including IL-11, OSM, LIF, CT-1, CNTF, and IL-27 (Fig. 5).23,24) Although the results had already exceeded my expectations, this was not the end of the story.


Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir.

Hirano T - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2010)

IL-6 receptor is composed of two subunits: an IL-6–specific alpha chain subunit and the signal transducer gp130.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3066534&req=5

fig04: IL-6 receptor is composed of two subunits: an IL-6–specific alpha chain subunit and the signal transducer gp130.
Mentions: After IL-6 was cloned, we isolated its receptor in the late 1980s. In fact, we cloned a cDNA encoding the IL-6 receptor using expression cloning, which had just been introduced by Brian Seed and his colleagues.62) Then, we cloned the signal-transducing receptor subunit gp130,63,64) demonstrating that the IL-6 receptor comprises an IL-6–specific alpha chain subunit and the gp130 signal transducer (Fig. 4). Interestingly, gp130 functions not only as a receptor subunit for IL-6, but also as a signal transducer for other cytokines, including IL-11, OSM, LIF, CT-1, CNTF, and IL-27 (Fig. 5).23,24) Although the results had already exceeded my expectations, this was not the end of the story.

Bottom Line: Characterization of IL-6 revealed a multifunctional cytokine that is involved in not only immune responses but also hematopoiesis, inflammation, and bone metabolism.F759 arthritis is dependent on CD4(+) T cells, IL-6, and IL-17A, and is enhanced by the pX gene product from human T cell leukemia virus 1 (HTLV-1).Furthermore, this interaction is mediated by the IL-6 amplifier through STAT3 and NF-kappaB.

View Article: PubMed Central - PubMed

Affiliation: JST-CREST, WPI Immunology Frontier Research Center, Osaka University, Japan. hirano@molonc.med.osaka-u.ac.jp

ABSTRACT
In this review, the author discusses the research that led to the identification and characterization of interleukin 6 (IL-6), including his own experience isolating IL-6, and the roles this cytokine has on autoimmune and inflammatory diseases. The cDNAs encoding B-cell stimulatory factor 2 (BSF-2), interferon (IFN)-beta2 and a 26-kDa protein were independently cloned in 1986, which in turn led to the identification of each. To resolve the confusing nomenclature, these identical molecules were named IL-6. Characterization of IL-6 revealed a multifunctional cytokine that is involved in not only immune responses but also hematopoiesis, inflammation, and bone metabolism. Moreover, IL-6 makes significant contributions to such autoimmune and inflammatory diseases as rheumatoid arthritis (RA).IL-6 activates both the STAT3 and SHP2/Gab/MAPK signaling pathways via the gp130 signal transducer. F759 mice, which contain a single amino-acid substitution in gp130 (Y759F) and show enhanced STAT3 activation, spontaneously develop a RA-like arthritis as they age. F759 arthritis is dependent on CD4(+) T cells, IL-6, and IL-17A, and is enhanced by the pX gene product from human T cell leukemia virus 1 (HTLV-1). Arthritis development in these mice requires that the F759 mutation is present in nonhematopoietic cells, but not in immune cells, highlighting the important role of the interaction between nonimmune tissues and the immune system in this disease. Furthermore, this interaction is mediated by the IL-6 amplifier through STAT3 and NF-kappaB. Ultimately, this model may represent a general etiologic process underlying other autoimmune and inflammatory diseases. More importantly, the understanding of IL-6 has paved the way for new therapeutic approaches for RA and other autoimmune and inflammatory diseases.

Show MeSH
Related in: MedlinePlus