IL-6 signal transduction and its physiological roles: the signal orchestration model

Abstract

Interleukin (IL)-6 is a pleiotropic cytokine that not only affects the immune system, but also acts in other biological systems and many physiological events in various organs. In a target cell, IL-6 can simultaneously generate functionally distinct or sometimes contradictory signals through its receptor complex, IL-6Ralpha and gp130. One good illustration is derived from the in vitro observations that IL-6 promotes the growth arrest and differentiation of M1 cells through gp130-mediated STAT3 activation, whereas the Y759/SHP-2-mediated cascade by gp130 stimulation has growth-enhancing effects. The final physiological output can be thought of as a consequence of the orchestration of the diverse signaling pathways generated by a given ligand. This concept, the signal orchestration model, may explain how IL-6 can elicit proinflammatory or anti-inflammatory effects, depending on the in vivo environmental circumstances. Elucidation of the molecular mechanisms underlying this issue is a challenging subject for future research. Intriguingly, recent in vivo studies indicated that the SHP-2-binding site- and YXXQ-mediated pathways through gp130 are not mutually exclusive but affect each other: a mutation at the SHP-2-binding site prolongs STAT3 activation, and a loss of STAT activation by gp130 truncation leads to sustained SHP-2/ERK MAPK phosphorylation. Although IL-6/gp130 signaling is a promising target for drug discovery for many human diseases, the interdependence of each signaling pathway may be an obstacle to the development of a nonpeptide orally active small molecule to inhibit one of these IL-6 signaling cascades, because it would disturb the signal orchestration. In mice, a consequence of the imbalanced signals causes unexpected results such as gastrointestinal disorders, autoimmune diseases, and/or chronic inflammatory proliferative diseases. However, lessons learned from IL-6 KO mice indicate that IL-6 is not essential for vital biological processes, but a significant impact on disease progression in many experimental models for human disorders. Thus, IL-6/gp130 signaling will become a more attractive therapeutic target for human inflammatory diseases when a better understanding of IL-6 signaling, including the identification of the conductor for gp130 signal transduction, is achieved.

Interleukin‐6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1

“…34,35 In our time course studies with IL-6-stimulated cells, phosphorylation of STAT3 at tyrosine 705 occurred after 5 min in both cell lines, NIH3T3 and U87MG (Fig. 3a).…”

“…46 IL-6 is known to signal primarily via the STAT and MAPK pathways. 35 In contrast to HGF-induced VEGF transcription, where Sp1 phosphorylation is dependent on PI3-K and MEK1/2 signalling, 47 pretreatment of NIH3T3 cells with either PD98059 or LY294002 led only to a 30% reduction of IL-6-triggered VEGF transcription (data not shown), suggesting that the MAPK and PI3-K/Akt signaling pathways are only partially involved. However, transfection of NIH3T3 cells and U87MG cells with dominant-negative STAT3 reduced IL-6-mediated VEGF expression to control levels, attesting that STAT3 is absolutely required for IL-6-regulated VEGF expression.…”

The LIM/Homeodomain Protein Islet1 Recruits Janus Tyrosine Kinases and Signal Transducer and Activator of Transcription 3 and Stimulates Their Activities

“…The interleukin (IL)-6 cytokine family, such as ciliary neurotrophic factor (CNTF), cardiotrophin, oncostatin M, and leukemia inhibitory factor (LIF), play pleiotropic roles in the immune and the hematopoietic systems, as well as in various aspects of neuronal development, including phenotype determination, survival, and response to nerve injury (reviewed in Schumann et al, 1999;Nakashima and Taga, 2002;Kamimura et al, 2003). The IL-6 -type cytokines bind to their specific receptor subunits, which leads to homodimerization of glycoprotein (gp) 130, a common receptor subunit, or heterodimerization of gp130 with gp130-related receptors, which results in the activation of the gp130-associated Janus kinases (JAKs).…”

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

“…Introduction IL-6 is a pluripotent cytokine secreted by various tissues and cells, such as immune cells, endothelial cells, myocytes and adipose cells [1,2], that mediate inflammatory and stress-induced responses. Circulating and adipose tissue IL-6 levels are increased in patients with obesity, insulin resistance and type 2 diabetes [3][4][5][6][7][8][9], the increased level correlating with degree of insulin resistance measured as insulin-stimulated glucose uptake [7][8][9].…”