IL-6: a pleiotropic cytokine

IL-6: a pleiotropic cytokine

IL-6 Overview

Interleukin-6 (IL-6) is a 21 kDa glycoprotein that was discovered in the 1980s. IL-6 was originally termed B cell stimulatory factor 2 and thought to be a member of the interferon (IFN) family; however, cloning of IL-6 led to the discovery that IL-6 does not have any IFN-inducing ability, and instead has since been identified to have many diverse functions including cell growth and robust pro-inflammatory responses (Hirano et al, 1988). IL-6 is primarily expressed by antigen presenting cells (APCs) such as macrophages and dendritic cells and B cells, although secretion is also described CD4+ T cells (Dienz et al, 2009; Hirano, 1998).

IL-6 Signalling

IL-6 binds to the transmembrane IL-6 receptor (IL-6R). The IL-6R interacts with a glycoprotein, termed gp130, at the membrane which facilitates its’ downstream signalling in the cytosol (Taga et al, 1989). The interaction between IL-6R and gp130 is not monogamous as gp130 has been shown to interact with several other cytokine receptors (Muller-Newman, 2003). The IL-6-mediated association of IL-6R and gp130 leads to the recruitment of several tyrosine kinases; Janus kinase 1 & 2 (JAK1 & JAK2) and tyrosine kinase 2 (Tyk2), which induces phosphorylation of signal transducer and activator of transcriptions 3 (STAT3) and translocation to the nucleus where multiple anti-apoptotic and cytokine-associated genes are transcribed (Akira, 1997) (see Figure 1). IL-6 signalling is negatively regulated by SOCS3 and STAT3, both of which are transcribed in and IL-6 dependent manner, demonstrating a negative feedback loop (Garbers et al, 2015; Croker et al, 2008). Crosstalk between cytokine pathways is common, and it has been described that both IL-6 and the potent anti-inflammatory cytokine IL-10 use a similar signalling mechanisms through STAT3 (Lai et al, 1996). IL-6 is produced in response to acute inflammation, primarily in response to simulation by TNFa, LPS, and IL-1 (Kamimura et al, 2003), and is a central regulator of maintaining chronic inflammation (Gabay, 2006). A proposed IL-6 – dependent shift from acute to chronic inflammation is mediated via the binding of IL-6 to the soluble IL-6 receptor, sIL-6Ra, leading to what has been termed as ‘trans-signalling’ and facilitates a sustained IL-6-induced inflammatory response, and the subsequent activation and infiltration of several mediators of sustained inflammation (Hurst et al, 2001).

The Role of IL-6 in Disease

High serum levels of IL-6 are associated with increased tumourigeneses (Lech-Maranda et al, 2006). IL-6 has a central role in inducing proliferation by inhibiting apoptosis, and studies inhibiting the IL-6/STAT3 pathway in vitro have reversed these anti-apoptotic functions in a multiple myeloma model (Chatterjee et al, 2004). IL-6 also has a detrimental role in the development of cancer, as it has been demonstrated that IL-6 induces the conversion of non-cancer cells into tumour stem cells (Kim et al, 2013). Furthermore, IL-6 is associated with the development of arthritis (Alonzi et al, 1998) and colitis (Atreya et al, 2000), with il-6-deficient mice susceptible to several bacterial pathogens, including Listeria monocytogenes and Candida albicans (Dalrymple et al, 1995; Romani et al, 1996).

IL-6 as an Inflammatory Target

As excess levels of IL-6 or the IL6R are associated with pathogeneses, blocking the IL-6R has revealed promising results in certain inflammatory diseases and cancer (Allocca et al, 2013; Coward et al, 2011). Targeting IL-6 signalling molecules is being explored as a therapeutic strategy (Aparicio-Siegmund et al, 2014). STAT3 inhibitors are currently being tested in clinical trials to treat various cancers, where the anti-apoptotic role of STAT3 is targeted (Page et al, 2011). Moreover, several efforts have been made to inhibit the activities of JAK1 and JAK2 in an effort to suppress the robust inflammatory response induced by the JAK/STAT pathway (Leonard and O’Shea, 1998), however an antibody specifically targeting the IL-6R, called tocilizumab, may prove to be more beneficial for treating inflammatory disease (Garbers et al, 2015). Additionally, another monoclonal antibody, targeting IL-6, called Siltuximab, has shown positive results in clinical trials treating prostate cancer and multiple myeloma (Dorff et al, 2010; Rossi et al, 2010).

The Role of IL-6 in T-Cell Differentiation

Although IL-6 alone is not described to induce T cell growth, its’ effects on T cell proliferation are mediated by the induction of anti-apoptotic molecules, demonstrated by the upregulation of Bcl-2 in isolated T cell populations (Teague et al, 1997). IL-6 may also mediate its effect on differentiating T cells subsets through downstream cytokine production (see Figure 2). Importantly, IL-6 is essential for fine tuning the CD4+ helper T cell response, by regulating the balance between the Th1 and Th2 responses (Diehl et al, 2000; Rincon et al, 1997). IL-6 downregulates IFNg production through the upregulation of SOCS1, which suppresses IFNg signalling, and therefore limits the differentiation of T-cells into the Th1 state (Diehl et al, 2000). IL-6 – induced transcription of NFATc leads to the upregulation of IL-4, which facilitates T-cell polarization towards the Th2 state (Heijink et al, 2002; Rincon et al, 1997). Additionally, IL-6 together with TGFb mediate increased levels of IL-17 through upregulating the receptor RORgt, which polarizes T cells towards the Th17 (Passos et al, 2010). Finally, IL-6 inhibits TGFb expression on CD4+ T cells, which prevents the differentiation into Tregs (Kuhn et al, 2017).

Figure 1: IL-6 signalling. IL-6 binds to the transmembrane IL-6 receptor (IL-6R), which induces the interaction between the glycoprotein gp130 and IL-6R, facilitating downstream interactions with the tyrosine kinases JAK1, JAK2 and Tyk2. These tyrosine kinases mediated signalling downstream and phosphorylates STAT3, inducing its’ nuclear translation and the transcription of multiple cytokine-related and anti-apoptotic genes, as well as the negative regulators of IL-6 signalling, SOC3 and STAT3.

Figure 2: Effects of IL-6 on T cell differentiation. IL-6 downregulates IFNg through the upregulation of the IFNg signalling suppressor, suppressor of cytokines 1 (SOCS1). Additionally, IL-6 mediates the transcription of IL-4, thus reducing T cell polarization to the Th1 subset and more towards the Th2 state. IL-6 in combination with TGFb leads to increased IL-17 production, facilitating the regulation of Th17 differentiation. IL-6 also inhibits CD4+ T cell expression of TGFb which limits the differentiation into the Treg state. (Adapted from Dienz and Rincon, 2009)


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