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IL-6 has captured the imagination of researchers in every field of biology and medicine since its multiple pathophysiological functions. It has been shown that IL-6 plays critical roles in various diseases together with its receptor system.
IL-6 signaling pathways
It is generally accepted that IL-6 effects its biological function via two signaling pathways, one called classical signaling and another called tran-signaling (Figure 1).
Figure 1. IL-6 signaling is a function of both classical IL-6 signaling and IL-6-trans-signaling. (Didion S P. 2017)
Studies have shown that the binding of IL-6 to IL-6 receptor (IL-6R) and subsequent dimerization of the membrane-bound gp130 are important steps in classical IL-6 signaling pathway. It has been reported that IL-6/IL-6R complex facilitates dimerization of gp130, which contains binding sites for recruitment and phosphorylation of signaling molecules, inducing activation of multiple down-stream signaling such as Janus-associated kinases (Jak), signal transducer and activator of transcription (STAT1), phosphatidylinositol-3-kinase (PI3K/Akt), to name but a few. All those signaling pathways make IL-6 a pleiotropic biological molecule involved in many physiological processes. For example, phosphorylated STAT molecules enter to the nucleus activating the transcription of IL-6-dependent genes such as Suppressor of cytokine signaling 3 (SOCS3). A number of studies have demonstrated that classical IL-6 pathway is particularly important for some cells such as hepatocytes, some leukocytes and microglia.
It has been well established that IL-6 trans-signaling plays a critical role in IL-6 biological functions in addition to classical signaling. Unlike classical signaling, IL-6 mediates trans-signaling through binding to soluble IL-6 receptor (sIL-6R), which is responsible for IL-6 signaling in tissues that express membrane-bound gp130 but not IL-6R. Studies have found that IL-6/sIL6R complex binds to gp130 and subsequent gp130/JAK activates the STAT3 pathway same as classical pathway. Moreover, soluble form of gp130 (sgp130) has been found to acts as a critical endogenous inhibitor of IL-6 signaling through binding with IL-6/sIL-6R complex competitive with membrane-bound gp130. It has shown that this pathway is implicated with a variety of cells including neural stem cells (NSCs), astroglia and oligodendroglia.
IL-6 and related physiologic/pathophysiologic process
IL-6 plays important roles in physiologic process but in addition has been shown to be intimately involved in a wide array of pathophysiologic process including tumor microenvironment, diabetic nephropathy, and Castleman disease.
Several reports have shown that IL-6 involves in many central nervous system (CNS) physiologic processes such as neuro protective and neuro regenerative effect, analgesic and allodynia effects, beneficial metabolic anti-obesity effects during health and metabolic impairment and neuroinflammation. Studies have found that IL-6 activation can be neurogenic and provides an avenue for the treatment of neurodegenerative diseases such as Parkinson’s disease. Additionally, it also has been that IL-6 is responsible for a wide range of effects in the vascular wall, such as endothelial activation, vascular permeability, immune cell recruitment and endothelial dysfunction. Furthermore, IL-6 also acts on promotion of endothelial dysfunction and vascular hypertrophy and fibrosis.
Figure 2. The diagram summarizing the major signaling pathways of IL-6 in cancers. (Liu Q, 2017)
Several reports have demonstrated that IL-6 involves in all pathophysiologic process of tumor cells range genes expression from proliferation, survival, invasion, differentiation as well as apoptosis. It has been shown that there are three major signaling pathways, PI3K/AKT and Ras/MAPK and STAT3, mediate the IL-6 function on tumor cells (Figure 2). Among the three pathways, STAT3 is related to target genes expression via binding with DNA elements. In contrast to STAT3, PI3K/AKT effects on gene regulation via activating NF-κB. Moreover, Ras/MAPK is responsible for regulating genes associated with cell growth stimulation and acute-phase protein and immunoglobulin synthesis. In addition, IL-6 is found to be related with cognitive impairment and metabolic changes in patients with schizophrenia. In fact, it has been shown that antipsychotic therapy induces serum IL-6 decreasing, which might be predisposing factor for the development of obesity and obesity-related metabolic disorders in schizophrenia. In addition to tumor cells and schizophrenia, IL-6 also effects on pituitary adenomas and Diabetic nephropathy (DN).