IL-6 as a pleiotropic cytokine

IL-6 was first identified as a differentiation factor for B cells which stimulates production of antibodies by activated B cells. Apart from regulation of acute inflammation, IL-6 is known to induce differentiation of B cells, and activation and population expansion of T cells [56]. Within the peripheral and central nervous system (CNS), IL-6 can act as a neuronal growth factor inducing neurite development and nerve regeneration [57]. IL-6 receptor (IL-6R) consists of the IL-6-binding chain which has two forms of transmembrane IL-6R and soluble IL-6R (sIL-6R) [58] and a gp130 signal-transducing chain [59]. Following binding to its receptor (IL-6R), IL-6 initiates to exert its multiple functions.

It is quite interesting that IL-6 exerts both pro- and anti-inflammatory properties [60, 61]. Indeed, its signaling is complex and can lead to both inflammatory and anti-inflammatory cascades depending upon the presence of either IL-6 receptor (IL-6R) or the membrane bound gp130 signal transducer and these are expressed at very different frequencies within specific cell type in the body [5]. Trans-signaling of IL-6, in which the soluble form of the IL-6 receptor (sIL-6R) is shed from the membrane bound receptors, is known to be pro-inflammatory [62]. The sIL-6R binds to IL-6 and is transported to any cell type on which gp130 is expressed [63]. While most soluble receptors (e.g., soluble receptor for TNFα) result in antagonistic action by competing for the ligand, the sIL-6R is agonistic and increases the types of cells through which IL-6 can signal. Additionally, IL-6 engages in classical signaling which is anti-inflammatory [63] and occurs through binding of IL-6 to the membrane bound cell surface receptor. Classical signaling of IL-6 solely occurs on some subsets of T cells, neutrophils and monocytes megakaryocytes, and hepatocytes [64]. In both classical and trans-signaling, the IL-6/IL-6R/gp130 complex uses two pathways to activate intracellular signaling namely the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and the mitogen-activated protein kinase (MAPK) pathway [5].

Indeed, IL-6 has been mostly regarded as having pro-inflammatory properties; however, it has many anti-inflammatory functions which are necessary for resolution of inflammation [65]. For instance, IL-6 inhibits activity of the transcription factor named nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and expression of the chemokine receptor on dendritic cells which is needed for recruiting these cells to lymphoid tissues; thus, involving in resolution of inflammation [66]. Research findings showed that IL-6 has a crucial role in regulation of T helper17 (Th17)/regulatory T (Treg) cells [67]. In the presence of TGF-β, IL-6 is a vital signal for differentiation of naive T cells into Th17 cells which in turn are implicated in induction of autoimmune diseases [68, 69], and result in local tissue injury in chronic inflammatory disorders [70]. On the contrary, IL-6 can strongly inhibit the TGF-β-induced differentiation of Treg cells which in turn results in inhibition of autoimmunity and protects against tissue damage [71]. Functional dichotomy of IL-6 indicates that it may be responsible for maintaining the balance between pro- and anti-inflammatory responses, while having tissue-specific properties at the periphery and in the CNS [72].