Interleukin-6, a mental cytokine

Abstract

Almost a quarter of a century ago, interleukin-6 (IL-6) was discovered as an inflammatory cytokine involved in B cell differentiation. Today, IL-6 is recognized to be a highly versatile cytokine, with pleiotropic actions not only in immune cells, but also in other cell types, such as cells of the central nervous system (CNS). The first evidence implicating IL-6 in brain-related processes originated from its dysregulated expression in several neurological disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. In addition, IL-6 was shown to be involved in multiple physiological CNS processes such as neuron homeostasis, astrogliogenesis and neuronal differentiation.

The molecular mechanisms underlying IL-6 functions in the brain have only recently started to emerge. In this review, an overview of the latest discoveries concerning the actions of IL-6 in the nervous system is provided. The central position of IL-6 in the neuroinflammatory reaction pattern, and more specifically, the role of IL-6 in specific neurodegenerative processes, which accompany Alzheimer's disease, multiple sclerosis and excitotoxicity, are discussed. It is evident that IL-6 has a dichotomic action in the CNS, displaying neurotrophic properties on the one hand, and detrimental actions on the other. This is in agreement with its central role in neuroinflammation, which evolved as a beneficial process, aimed at maintaining tissue homeostasis, but which can become malignant when exaggerated. In this perspective, it is not surprising that ‘well-meant’ actions of IL-6 are often causing harm instead of leading to recovery.

Introduction

IL-6 was originally discovered as a factor produced by lymphocytes that stimulated the final maturation of B cells to antibody-producing cells (Hirano et al., 1986). Since its early characterization in the eighties (Haegeman et al., 1986, Hirano et al., 1985, Hirano et al., 1986, Hirano et al., 1987, May et al., 1986, Poupart et al., 1987, Van Damme et al., 1987, Yasukawa et al., 1987, Zilberstein et al., 1986), IL-6 has been implicated in an ever-growing array of processes, which include, among others, hematopoiesis, the acute phase response, liver regeneration, bone remodeling, metabolic processes and gliogenesis. IL-6 expression is furthermore dysregulated in diseases like atherosclerosis and asthma; in autoimmune diseases such as Crohn's disease, rheumatoid arthritis, diabetes and multiple sclerosis (MS); in different neurological disorders; and in various cancers such as multiple myeloma and glioma (Hirano et al., 1990). Although IL-6 was originally considered to be a pro-inflammatory cytokine, several discoveries prompted a revision of its characteristics and indicated that IL-6 also has anti-inflammatory properties. For instance, IL-6 inhibits neutrophil accumulation after lipopolysaccharide (LPS) injection and antagonizes the actions of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) via induction of the soluble IL-1 receptor antagonist and the soluble TNF-α receptor (Tilg et al., 1994, Ulich et al., 1991). Furthermore, IL-6 is required to control the levels of pro-inflammatory cytokines, such as TNF-α, in vivo after endotoxic insults, both locally and systemically (Xing et al., 1998). Under certain conditions IL-6 obtains anti-inflammatory characteristics in macrophages (Yasukawa et al., 2003). Finally, IL-6 is crucially involved in the induction and regulation of a novel type of T cells, the so-called Th17 cells, which are important players in autoimmune reactions (further discussed under Section 5.1.3).

Ever since the initial suggestion that IL-6 can function as a neurotrophic factor (Wagner, 1996), an important role for IL-6 in the CNS has emerged. It was discovered that a vast range of stimuli, varying from neurotransmitters over depolarization to other inflammatory cytokines, is able to induce IL-6 production in the brain. The main transcription factors regulating IL-6 expression, both in the periphery and the CNS, are nuclear factor κB (NF-κB), activator protein 1 (AP-1), cAMP response element binding protein (CREB) and CCAAT/enhancer-binding protein β (C/EBPβ, also known as NF-IL-6) (Dendorfer et al., 1994). In the CNS microglia and astrocytes, as well as neurons, produce IL-6 in different brain regions. In the late nineties these novel discoveries led to a surge in review papers describing the role of IL-6 in the CNS (Gadient and Otten, 1997, Gruol and Nelson, 1997, Munoz-Fernandez and Fresno, 1998, Van Wagoner and Benveniste, 1999). Since then, no comprehensive review paper describing the novel functions of IL-6 in the CNS has been published, although more specific aspects of IL-6 functioning in the nervous system have been reviewed, such as for instance the role of IL-6 in ischemia (Suzuki et al., 2009) and spinal cord injury (Nakamura et al., 2005). This review paper aims at recapitulating the most recent developments in the field of CNS-originated IL-6 research. We will put special emphasis on the examination of the different molecular pathways underlying the (patho)physiological actions of IL-6 in the CNS.

IL-6 belongs to a cytokine family of which all the members share a common signal transducer, namely gp130 (glycoprotein 130, also known as CD130). Although the different family members display little amino acid homology, they all possess a similar tertiary structure, composed of 4 α-helices with an up–up–down–down topology. Other members of this family include: ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), neuropoietin (NPN), IL-11, IL-27 and IL-31. Of this family, several members have a distinct role in the CNS, such as LIF and CNTF; and there is, at least partial, redundancy among the different family members. The IL-6 family members bind to their respective membrane receptors and this subsequently induces dimerization of the signal-transducer protein gp130. IL-6 binds to the non-signaling IL-6 receptor α (IL-6R, also known as gp80 or CD126), which induces homodimerization of gp130. Apart from IL-6 and IL-11, the other IL-6 family members all bind to signal-transducing receptors, such as LIFR or OSMR, and binding induces heterodimerization of these receptors with gp130. In both cases, dimerization is followed by activation of the associated Janus kinases (JAK-1 and JAK-2), which phosphorylate specific conserved tyrosine residues in the cytoplasmic domains of gp130. In this way, recruitment sites for signal transducer and activator of transcription proteins (STATs) are formed. Once recruited, these STATs are phosphorylated by JAKs and this induces dimerization of STATs and their subsequent translocation to the nucleus where they modulate gene transcription. There are seven different STAT subtypes, two of which can bind gp130, namely STAT-1 and STAT-3. Although in vitro IL-6 can activate both STAT-1 and STAT-3 in primary astrocytes (Jenab and Quinones-Jenab, 2002), in vivo studies point out that STAT-1 only has a minimal role in IL-6 signaling (Sanz et al., 2008). The majority of studies indeed indicate that IL-6 signaling in the CNS is carried out by STAT-3. Interestingly, a self-regulating mechanism for control of IL-6 signaling has been described recently in glial cells (Rose et al., 2009). Both IL-6 and other cytokine mixtures, induce down-regulation of gp130. This is a rather late effect, and it was suggested that early effects of IL-6 signaling would thus not be influenced, whereas late effects would be blunted. Apart from the JAK–STAT pathway, another major signaling cascade that is activated by IL-6 family cytokines is the mitogen-activated protein kinase (MAPK) pathway. Phosphorylation of a specific tyrosine residue of gp130 by JAKs induces binding of SHP2, followed by grb2-SOS-mediated activation of the Ras–Raf–MAPK pathway. A third signaling cascade activated by IL-6 is the PI-3K/Akt pathway, but this pathway is, up to now, not very well characterized in the context of IL-6 effects in the CNS. Several excellent reviews exist on IL-6 signaling to which we refer for more detailed knowledge (Heinrich et al., 1998, Heinrich et al., 2003). A schematic representation of the main signaling pathways activated by IL-6 in the CNS can be found in Fig. 1.

A special feature of IL-6 signaling is the existence of the soluble IL-6 receptor (sIL-6R). The sIL-6R was initially discovered in urine (Novick et al., 1989) and later also in plasma (Honda et al., 1992), and is generated via either alternative splicing of IL-6R mRNA (Lust et al., 1992), or shedding of the membrane receptor (Mullberg et al., 1993). The protease responsible for cleavage of the IL-6R remains unidentified up to now, although it was shown that the phorbolester PMA enhances IL-6R shedding (Mullberg et al., 1994) and that this process can be partially blocked by a TNF-α protease inhibitor (Mullberg et al., 1995). Soluble forms of other cytokine receptors have been reported, such as of IL-1 and TNF-α. However, the sIL-6R presents an unusual case since it has agonistic properties, instead of the usual antagonistic features of other soluble cytokine receptors. Although gp130 is a protein that is ubiquitously present, IL-6R expression is much more restricted. The generation of sIL-6R is thus a powerful mechanism for conferring IL-6 responsiveness to cells lacking IL-6R. This so-called process of transsignaling has been suggested to be of particular importance in the CNS (Marz et al., 1999b, Schobitz et al., 1995), and the elevation of the sIL-6R in a number of diseases suggest a role in several pathophysiological processes (Jones et al., 2001). To further complicate matters, a soluble form of gp130, sgp130, also exists. In the presence of sgp130, sIL-6R exerts antagonistic properties: due to the complexing of IL-6 by both sIL-6R and sgp130, IL-6 signaling is inhibited. Based on the naturally occurring process of transsignaling, a designer cytokine, named Hyper-IL-6, has been created, which consists of a fusion between IL-6 and the sIL-6R (Fischer et al., 1997). This cytokine allows investigation of the IL-6 response in cells lacking the IL-6R. This is particularly relevant for cells that respond to IL-6 in vivo after generation of sIL-6R via, for example, shedding by neighboring cells, since these cells will show no response to IL-6 in isolated in vitro cultures.

IL-6 has emerged as a pivotal player in the nervous system as is evident from its essential involvement in neuroinflammation, neurotrophic processes and several nervous system pathologies.