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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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IL-6 together with TGFβ induces Th17 cell development, a pivotal step in the development of autoimmune diseases and inflammation.
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fig11: IL-6 together with TGFβ induces Th17 cell development, a pivotal step in the development of autoimmune diseases and inflammation.

Mentions: Classification of CD4+ T cells into T helper 1 (Th1) and Th2 cells has provided a framework for understanding the contributions of various CD4+ T cell subtypes to autoimmune diseases.68–70) Furthermore, recent studies have identified Th17 cells as a previously unknown arm of the CD4+ T cell effector response (Fig. 11). These cells secrete several proinflammatory cytokines, including IL-17A, an important cytokine in such autoimmune diseases as collagen-induced arthritis, experimental autoimmune encephalomyelitis (EAE), and the arthritis disorders that develop in SKG and IL-1 receptor antagonist–deficient mice.71–74) F759 arthritis is also dependent on IL-17A.75) Another T cell subset, Treg cells, has been shown to regulate immune responses, while abnormalities in these cells cause autoimmune diseases.76) Additionally, IL-6 together with TGF-β induces Th17 cell development, whereas TGF-β induces Treg cell development. Thus, IL-6 is a key cytokine involved in T cell differentiation (Fig. 11).30,31) We have shown that gp130 and STAT3 in T cells are essential for Th17 development.34) Taken together, these results indicate that IL-6 makes significant contributions to both normal immune responses and autoimmune diseases.


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

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

IL-6 together with TGFβ induces Th17 cell development, a pivotal step in the development of autoimmune diseases and inflammation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig11: IL-6 together with TGFβ induces Th17 cell development, a pivotal step in the development of autoimmune diseases and inflammation.
Mentions: Classification of CD4+ T cells into T helper 1 (Th1) and Th2 cells has provided a framework for understanding the contributions of various CD4+ T cell subtypes to autoimmune diseases.68–70) Furthermore, recent studies have identified Th17 cells as a previously unknown arm of the CD4+ T cell effector response (Fig. 11). These cells secrete several proinflammatory cytokines, including IL-17A, an important cytokine in such autoimmune diseases as collagen-induced arthritis, experimental autoimmune encephalomyelitis (EAE), and the arthritis disorders that develop in SKG and IL-1 receptor antagonist–deficient mice.71–74) F759 arthritis is also dependent on IL-17A.75) Another T cell subset, Treg cells, has been shown to regulate immune responses, while abnormalities in these cells cause autoimmune diseases.76) Additionally, IL-6 together with TGF-β induces Th17 cell development, whereas TGF-β induces Treg cell development. Thus, IL-6 is a key cytokine involved in T cell differentiation (Fig. 11).30,31) We have shown that gp130 and STAT3 in T cells are essential for Th17 development.34) Taken together, these results indicate that IL-6 makes significant contributions to both normal immune responses and autoimmune diseases.

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