Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir

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.

Figure 1.

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.

Figure 2.

At a nomenclature meeting chaired by Dr. W. E. Paul, the name “interleukin-6” was proposed for these synonymous molecules (Dec. 14, 1988; New York).⁵⁶⁾

Figure 3.

Multifunctional cytokine IL-6 is produced by a variety of cell types, including T cells, B cells, macrophages, astrocytes, stromal cells, vascular endothelial cells, smooth muscle cells, and fibroblasts. IL-6 induces antibody expression (B cell stimulatory factor 2) and cytotoxic T-lymphocyte activity (T cell activation factor). IL-6 was also referred to as a hybridoma/plasmacytoma growth factor and a hepatocyte stimulatory factor. IL-6 acts as a growth factor for AIDS-related Kaposi’s sarcoma, mesangial cells, and renal cell carcinomas, and as a thrombopoietin, a nerve growth factor, a hormone-inducing factor in the pituitary gland, an osteoclast-inducing factor, and a keratinocyte growth factor.

Figure 4.

IL-6 receptor is composed of two subunits: an IL-6–specific alpha chain subunit and the signal transducer gp130.

Figure 5.

gp130 is not only a receptor subunit for IL-6, but also functions as a signal transducer for other cytokines like IL-11, OSM, LIF, CT-1, CNTF, and IL-27.

Figure 6.

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

Figure 7.

A working hypothesis for the mechanisms involved in certain autoimmune diseases and CIPD. During the initial phase, inflammation and transcription factor activation can be induced by a variety of stimuli, including infection, foreign materials, and/or injury, leading to the expression of IL-6 and other cytokines, MHC molecules, adhesion molecules, autoantigens, and transcription factors. Autoantigens in the context of MHC molecules may be recognized by autoreactive T cells, activating the T cells to propagate the inflammatory response. Because the first phase can occur in nonimmune cells or tissues, this model implies that interactions between nonimmune and the immune systems may play critical roles in autoimmune diseases and CIPD.

Figure 8.

IL-6 induces two major signal transduction pathways, STAT3 signaling and SHP2/Gab/MAPK signaling. Activation of these pathways depends on the gp130 YxxQ motives and Y759, respectively.

Figure 9.

F759 mice show enhanced STAT3 activation in response to IL-6 owing to the Y759F mutation in gp130, which inhibits SOCS3-mediated negative feedback. These mutant mice spontaneously develop a RA-like joint disease (F759 arthritis). Characteristics of the disease are included in the figure: late onset; nearly 100% incidence; symmetrical, chronic, and progressive symptoms; infiltration of neutrophils into the joints; hyperplasia of synovial fibroblasts; pannus formation and the presence of activated osteoclasts; joint destruction and ankylosis; splenomegaly and lymphadenopathy; hypergammaglobulinemia; autoantibody productions; increased numbers of memory/activated T cells, granulocytes, plasma cells, and immature dendritic cells; resistance to super antigen-induced T cell death; and a requirement for lymphocytes during disease development.

Figure 10.

Interactions between nonimmune tissues and the immune system play critical etiologic roles in autoimmune diseases. The F759 mutation in nonimmune cells, particularly in type 1 collagen⁺ fibroblasts, induces excessive IL-7 production, followed by activation of CD4⁺ T cells in the presence of dendritic cells. Activated CD4⁺ T cells express cytokines, including IL-17A, TNF-α, and IL-6, which leads to the development of arthritis.

Figure 11.

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

Figure 12.

The IL-6 amplifier plays a critical role in F759 arthritis.

Figure 13.

Any factor that activates STAT3 and/or NF-κB in a nonimmune tissue outside of the immune system may trigger autoimmune diseases or CIPD through dysregulation of the IL-6 amplifier.