The Paradigm of IL-6: from Basic Science to Medicine

Overview

Journal Arthritis Res

Specialty Rheumatology

Date 2002 Jul 12

PMID 12110143

Citations 162

Authors

Tetsuji Naka

Norihiro Nishimoto

Tadamitsu Kishimoto

Affiliations

Soon will be listed here.

Abstract

IL-6 is a pleiotropic cytokine with a wide range of biological activities in immune regulation, hematopoiesis, inflammation, and oncogenesis. Its activities are shared by IL-6-related cytokines such as leukemia inhibitory factor and oncostatin M. The pleiotropy and redundancy of IL-6 functions have been identified by using a unique receptor system comprising two functional proteins: an IL-6 receptor (IL-6R) and gp130, the common signal transducer of cytokines related to IL-6. Signal transduction through gp130 is mediated by two pathways: the JAK-STAT (Janus family tyrosine kinase-signal transducer and activator of transcription) pathway and the Ras mitogen-activated protein kinase pathway. The negative regulators of IL-6 signaling have also been identified, although the physiological roles of the molecules are not yet fully understood. The pathological roles of IL-6 have also been clarified in various disease conditions, such as inflammatory, autoimmune, and malignant diseases. On the basis of the findings, a new therapeutic approach to block the IL-6 signal using humanized anti-IL-6R antibody for rheumatoid arthritis, Castleman's disease, and multiple myeloma has been attempted.

Citing Articles

Oral Microbiome: A Review of Its Impact on Oral and Systemic Health.

Rajasekaran J, Krishnamurthy H, Bosco J, Jayaraman V, Krishna K, Wang T Microorganisms. 2024; 12(9).

PMID: 39338471 PMC: 11434369. DOI: 10.3390/microorganisms12091797.

Application of biological agents in the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis.

Liu W, Tian G, Chen C, Zhang M, Chen Z, Chen T Front Pharmacol. 2024; 15:1378384.

PMID: 38831887 PMC: 11144864. DOI: 10.3389/fphar.2024.1378384.

Autocrine Regulation of Interleukin-6 via the Activation of STAT3 and Akt in Cardiac Myxoma Cells.

Jougasaki M, Takenoshita Y, Umebashi K, Yamamoto M, Sudou K, Nakashima H Int J Mol Sci. 2024; 25(4).

PMID: 38396907 PMC: 10888597. DOI: 10.3390/ijms25042232.

Chronic Inflammation, Oxidative Stress and Metabolic Plasticity: Three Players Driving the Pro-Tumorigenic Microenvironment in Malignant Mesothelioma.

Fiorilla I, Martinotti S, Todesco A, Bonsignore G, Cavaletto M, Patrone M Cells. 2023; 12(16).

PMID: 37626858 PMC: 10453755. DOI: 10.3390/cells12162048.

Macrophage migration inhibitory factor (MIF) and its homolog D-dopachrome tautomerase (D-DT) are significant promotors of UVB- but not chemically induced non-melanoma skin cancer.

Huth S, Huth L, Heise R, Marquardt Y, Lopopolo L, Piecychna M Sci Rep. 2023; 13(1):11611.

PMID: 37464010 PMC: 10354066. DOI: 10.1038/s41598-023-38748-9.

References

Miki S, Iwano M, Miki Y, Yamamoto M, Tang B, Yokokawa K . Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas. FEBS Lett. 1989; 250(2):607-10. DOI: 10.1016/0014-5793(89)80805-1. View

Sato K, Tsuchiya M, Saldanha J, Koishihara Y, Ohsugi Y, Kishimoto T . Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth. Cancer Res. 1993; 53(4):851-6. View

Hilton D, Richardson R, Alexander W, Viney E, Willson T, Sprigg N . Twenty proteins containing a C-terminal SOCS box form five structural classes. Proc Natl Acad Sci U S A. 1998; 95(1):114-9. PMC: 18144. DOI: 10.1073/pnas.95.1.114. View

Baumann H, Wong G . Hepatocyte-stimulating factor III shares structural and functional identity with leukemia-inhibitory factor. J Immunol. 1989; 143(4):1163-7. View

Uyttenhove C, Coulie P, Van Snick J . T cell growth and differentiation induced by interleukin-HP1/IL-6, the murine hybridoma/plasmacytoma growth factor. J Exp Med. 1988; 167(4):1417-27. PMC: 2188915. DOI: 10.1084/jem.167.4.1417. View

Zilberstein A, Ruggieri R, Korn J, Revel M . Structure and expression of cDNA and genes for human interferon-beta-2, a distinct species inducible by growth-stimulatory cytokines. EMBO J. 1986; 5(10):2529-37. PMC: 1167149. DOI: 10.1002/j.1460-2075.1986.tb04531.x. View

Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B . Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 1988; 18(11):1797-801. DOI: 10.1002/eji.1830181122. View

Stanley E, Bartocci A, Patinkin D, Rosendaal M, Bradley T . Regulation of very primitive, multipotent, hemopoietic cells by hemopoietin-1. Cell. 1986; 45(5):667-74. DOI: 10.1016/0092-8674(86)90781-6. View

Muraguchi A, Kishimoto T, Miki Y, Kuritani T, Kaieda T, Yoshizaki K . T cell-replacing factor- (TRF) induced IgG secretion in a human B blastoid cell line and demonstration of acceptors for TRF. J Immunol. 1981; 127(2):412-6. View

10.

Nicola N, Metcalf D, Matsumoto M, Johnson G . Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells. Identification as granulocyte colony-stimulating factor. J Biol Chem. 1983; 258(14):9017-23. View

11.

Metcalf D, Greenhalgh C, Viney E, Willson T, Starr R, Nicola N . Gigantism in mice lacking suppressor of cytokine signalling-2. Nature. 2000; 405(6790):1069-73. DOI: 10.1038/35016611. View

12.

Horii Y, Muraguchi A, Iwano M, Matsuda T, Hirayama T, Yamada H . Involvement of IL-6 in mesangial proliferative glomerulonephritis. J Immunol. 1989; 143(12):3949-55. View

13.

Andus T, Geiger T, Hirano T, Northoff H, Ganter U, Bauer J . Recombinant human B cell stimulatory factor 2 (BSF-2/IFN-beta 2) regulates beta-fibrinogen and albumin mRNA levels in Fao-9 cells. FEBS Lett. 1987; 221(1):18-22. DOI: 10.1016/0014-5793(87)80344-7. View

14.

Yoshizaki K, Nishimoto N, Mihara M, Kishimoto T . Therapy of rheumatoid arthritis by blocking IL-6 signal transduction with a humanized anti-IL-6 receptor antibody. Springer Semin Immunopathol. 1998; 20(1-2):247-59. DOI: 10.1007/BF00832010. View

15.

Wendling D, Racadot E, Wijdenes J . Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal antibody. J Rheumatol. 1993; 20(2):259-62. View

16.

Ogawa M . Differentiation and proliferation of hematopoietic stem cells. Blood. 1993; 81(11):2844-53. View

17.

Baumann H, Onorato V, Gauldie J, Jahreis G . Distinct sets of acute phase plasma proteins are stimulated by separate human hepatocyte-stimulating factors and monokines in rat hepatoma cells. J Biol Chem. 1987; 262(20):9756-68. View

18.

Zhong Z, Wen Z, Darnell Jr J . Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994; 264(5155):95-8. DOI: 10.1126/science.8140422. View

19.

Ikebuchi K, Wong G, Clark S, Ihle J, Hirai Y, Ogawa M . Interleukin 6 enhancement of interleukin 3-dependent proliferation of multipotential hemopoietic progenitors. Proc Natl Acad Sci U S A. 1987; 84(24):9035-9. PMC: 299686. DOI: 10.1073/pnas.84.24.9035. View

20.

Guschin D, Rogers N, Briscoe J, Witthuhn B, Watling D, Horn F . A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. EMBO J. 1995; 14(7):1421-9. PMC: 398228. DOI: 10.1002/j.1460-2075.1995.tb07128.x. View