The paradigm of IL-6: from basic science to medicine

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.

Figure 1

IL-6-producing cells and biological activities of IL-6. IL-6 is produced by lymphoid and nonlymphoid cells, such as T cells, B cells, monocytes, fibroblasts, keratinocytes, endothelial cells, mesangial cells, and several kinds of tumor cell (top of figure). IL-6 also has a wide range of biological activities on various target cells (bottom of figure).

Figure 2

Schematic structure of gp130. Binding of IL-6 to IL-6R induces homodimerization of gp130, activating JAK associating with gp130 at Box1. This is followed by the tyrosine phosphorylation of the distal part of gp130 and recruitment of STAT3. STAT3 is then tyrosine-phosphorylated by JAK. SHP-2 on the second tyrosine (Y2) residue of gp130 activates the MAP kinase pathway. JAK, Janus family tyrosine kinase; SHP-2, Src homology protein 2 tyrosine phosphatase-2; STAT, signal transducer and activator of transcription; Y(2,3, etc.), (second, third, etc.) tyrosine residue (from the membrane).

Figure 3

Molecular mechanism of inhibition by new cytokine inhibitors. (Left) PIAS inhibits DNA-binding activity of STATs through association with activated them. (Center) SOCS-1 inhibits catalytic activity of JAKs by direct interaction with them. (Right) SOCS-3 inhibits catalytic activity of JAKs by binding to receptor complex. JAK, Janus family tyrosine kinases; P, phosphorylation; PIAS, protein inhibitors of activated STATs; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; Y, tyrosine residue.

Figure 4

Representative clinical course of an RA patient treated with humanized anti-IL-6R antibody. A 51-year-old woman with RA was given humanized anti-IL-6R antibody intravenously (50 mg twice a week). Although she had active disease refractory to conventional treatment with drugs including methotrexate and prednisolone, treatment with humanized anti-IL-6R remarkably improved her condition. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RF, rheumatoid factor.