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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

High levels of IL-6 are present in the synovial fluids of RA patients.11) OA, osteoarthritis.
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fig06: High levels of IL-6 are present in the synovial fluids of RA patients.11) OA, osteoarthritis.

Mentions: Patients with cardiac myxoma show a variety of autoimmune symptoms, such as hypergammaglobulinemia, the presence of autoantibodies, and increased acute-phase protein levels. Each of these symptoms is ameliorated when the tumor cells are resected, suggesting that cardiac myxoma cells induce autoimmunity. We found that cardiac myxoma cells produce IL-6,45) providing the first evidence of a role for IL-6 in an autoimmune disease. We then found that patients with RA have high synovial levels of IL-6 (Fig. 6),11) suggesting, for the first time, that IL-6 is involved in RA, a chronic autoimmune polyarthritis. Although both genetic and environmental factors contribute to this disease, the specific etiology is unknown. Patients with RA show a variety of symptoms, including polyclonal plasmacytosis accompanied by the production of rheumatoid factor, increased levels of acute-phase proteins, enhanced bone resorption, and increased platelet numbers, all of which do not at first glance appear closely related. The pleiotropic nature of IL-6, however, may shed some light on this puzzle. I speculated that dysregulation of IL-6 gene expression or activity is intimately related to the development of RA.7,65)


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

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

High levels of IL-6 are present in the synovial fluids of RA patients.11) OA, osteoarthritis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig06: High levels of IL-6 are present in the synovial fluids of RA patients.11) OA, osteoarthritis.
Mentions: Patients with cardiac myxoma show a variety of autoimmune symptoms, such as hypergammaglobulinemia, the presence of autoantibodies, and increased acute-phase protein levels. Each of these symptoms is ameliorated when the tumor cells are resected, suggesting that cardiac myxoma cells induce autoimmunity. We found that cardiac myxoma cells produce IL-6,45) providing the first evidence of a role for IL-6 in an autoimmune disease. We then found that patients with RA have high synovial levels of IL-6 (Fig. 6),11) suggesting, for the first time, that IL-6 is involved in RA, a chronic autoimmune polyarthritis. Although both genetic and environmental factors contribute to this disease, the specific etiology is unknown. Patients with RA show a variety of symptoms, including polyclonal plasmacytosis accompanied by the production of rheumatoid factor, increased levels of acute-phase proteins, enhanced bone resorption, and increased platelet numbers, all of which do not at first glance appear closely related. The pleiotropic nature of IL-6, however, may shed some light on this puzzle. I speculated that dysregulation of IL-6 gene expression or activity is intimately related to the development of RA.7,65)

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