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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

PPD-stimulated pleural effusion cells produce soluble factors capable of inducing immunoglobulin production in B cells. The culture supernatant from the pleural effusion cells or tonsillar mononuclear cells contained an active factor that had the same biologic and physicochemical properties of the cytokine now known as IL-6.
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fig01: PPD-stimulated pleural effusion cells produce soluble factors capable of inducing immunoglobulin production in B cells. The culture supernatant from the pleural effusion cells or tonsillar mononuclear cells contained an active factor that had the same biologic and physicochemical properties of the cytokine now known as IL-6.

Mentions: The research I was conducting there demonstrated that purified protein derivative (PPD)-stimulated pleural effusion cells from patients with pulmonary tuberculosis produced soluble factors capable of inducing immunoglobulin production in B cells (Fig. 1).38) Because this activity appeared to be very robust and a large number of lymphocytes could be obtained from each patient (up to 1 × 109 cells/patient), I decided to isolate the active factor and began to devise a purification protocol in 1978. In early 1980, Muraguchi, Kishimoto, and their colleagues,39) as well as Teranishi, myself, and our colleagues40) independently showed that culture supernatant fractions from stimulated human peripheral blood mononuclear cells and tonsillar mononuclear cells, respectively, induce immunoglobulin production in Epstein-Barr virus–transformed B lymphoblastoid cell lines. Kishimoto’s group called this factor “TRF” or “BCDF”,39,41) whereas our group called it “TRF-like factor” or “BCDFII”.40,42,43) We partially purified the TRF-like factor and showed that it was present in gel filtration fractions corresponding to molecular weights of 22 kDa and 36 kDa, and that its isoelectric point was between 5 and 6 (Fig. 1).40) The biological activity and physicochemical properties of the soluble factor were the same as those of a cytokine, now known as IL-6.7) I moved to Kumamoto University Medical School in 1980 as an Associate Professor in Dr. Onoue’s laboratory where I continued my efforts to purify and characterize this factor. In early 1984, I began working at Osaka University as an Associate Professor in Dr. Kishimoto’s laboratory and by the end of the year, finally succeeded in purifying the factor and determining the sequence of its 14 N-terminal amino acids.44,45) This success allowed me a brief reprieve from my work just before the new year. The next steps, however, were much harder than I expected. Several attempts to clone cDNA encoding the active protein completely failed. This raised the possibility that the identified sequence may have been incorrect or may have represented other proteins that had been co-purified with the active molecule. These worries gave me serious ill including a severe arrhythmia and kept me up at night through to the end of 1985. Thankfully, a medical checkup showed that my arrhythmia was psychogenic. I then attempted to purify the protein using 100 liters of newly obtained culture supernatants. We were lucky enough to obtain several protein fragments and their partial amino-acid sequences in March, 1986. Then, to clone the cDNA, we used three probes corresponding to three purified protein fragments. I speculated that this approach was more likely to succeed than using only one probe that corresponded to the N-terminal portion of the protein.


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

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

PPD-stimulated pleural effusion cells produce soluble factors capable of inducing immunoglobulin production in B cells. The culture supernatant from the pleural effusion cells or tonsillar mononuclear cells contained an active factor that had the same biologic and physicochemical properties of the cytokine now known as IL-6.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: PPD-stimulated pleural effusion cells produce soluble factors capable of inducing immunoglobulin production in B cells. The culture supernatant from the pleural effusion cells or tonsillar mononuclear cells contained an active factor that had the same biologic and physicochemical properties of the cytokine now known as IL-6.
Mentions: The research I was conducting there demonstrated that purified protein derivative (PPD)-stimulated pleural effusion cells from patients with pulmonary tuberculosis produced soluble factors capable of inducing immunoglobulin production in B cells (Fig. 1).38) Because this activity appeared to be very robust and a large number of lymphocytes could be obtained from each patient (up to 1 × 109 cells/patient), I decided to isolate the active factor and began to devise a purification protocol in 1978. In early 1980, Muraguchi, Kishimoto, and their colleagues,39) as well as Teranishi, myself, and our colleagues40) independently showed that culture supernatant fractions from stimulated human peripheral blood mononuclear cells and tonsillar mononuclear cells, respectively, induce immunoglobulin production in Epstein-Barr virus–transformed B lymphoblastoid cell lines. Kishimoto’s group called this factor “TRF” or “BCDF”,39,41) whereas our group called it “TRF-like factor” or “BCDFII”.40,42,43) We partially purified the TRF-like factor and showed that it was present in gel filtration fractions corresponding to molecular weights of 22 kDa and 36 kDa, and that its isoelectric point was between 5 and 6 (Fig. 1).40) The biological activity and physicochemical properties of the soluble factor were the same as those of a cytokine, now known as IL-6.7) I moved to Kumamoto University Medical School in 1980 as an Associate Professor in Dr. Onoue’s laboratory where I continued my efforts to purify and characterize this factor. In early 1984, I began working at Osaka University as an Associate Professor in Dr. Kishimoto’s laboratory and by the end of the year, finally succeeded in purifying the factor and determining the sequence of its 14 N-terminal amino acids.44,45) This success allowed me a brief reprieve from my work just before the new year. The next steps, however, were much harder than I expected. Several attempts to clone cDNA encoding the active protein completely failed. This raised the possibility that the identified sequence may have been incorrect or may have represented other proteins that had been co-purified with the active molecule. These worries gave me serious ill including a severe arrhythmia and kept me up at night through to the end of 1985. Thankfully, a medical checkup showed that my arrhythmia was psychogenic. I then attempted to purify the protein using 100 liters of newly obtained culture supernatants. We were lucky enough to obtain several protein fragments and their partial amino-acid sequences in March, 1986. Then, to clone the cDNA, we used three probes corresponding to three purified protein fragments. I speculated that this approach was more likely to succeed than using only one probe that corresponded to the N-terminal portion of the protein.

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