IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer

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Abstract

IL-6 activates various cell types carrying the membrane bound IL-6R (classical IL-6 signaling) as well as IL-6R gp130+ cells via the soluble IL-6R (IL-6 trans-signaling). IL-6 signaling plays a pivotal role in controlling the differentiation and activation of T lymphocytes by inducing the Jak/STAT-3 and the Ras/Erk/C/EBP pathways. In particular, IL-6 modulates the resistance of T cells against apoptosis, induces activation of T helper cells and controls the balance between regulatory T cells and Th17 cells. Importantly, recent findings suggest that blockade of IL-6 signaling is effective in treating experimental models of autoimmune and chronic inflammatory diseases such as inflammatory bowel diseases, diabetes, multiple sclerosis, asthma and rheumatoid arthritis as well as models of inflammation-associated cancer. Thus, anti-IL-6/anti-IL-6R strategies emerge as promising novel approaches for therapy of inflammatory diseases in humans. In this review article, we discuss the latest findings on the role of IL-6 in experimental models of autoimmunity and cancer, as well as clinical perspectives.

Introduction

Interleukin-6 (IL-6) was discovered in 1986 by Hirano and Kishimoto as a B cell stimulatory factor driving IgG production [1]. Subsequently, it was found that this multifunctional NF-kappaB-regulated cytokine can activate various cell types carrying gp130 and the membrane bound IL-6 receptor (classical IL-6 signaling via mIL-6R). However, also cells lacking the membrane bound IL-6R can respond to IL-6. Hereby, IL-6 binds to the soluble IL-6R (sIL-6R) before the IL-6/sIL-6R complex can bind to the gp130 molecule on IL-6R target cells [2]. This so-called IL-6 trans-signaling represents an alternative to classical IL-6 signaling and permits IL-6 to modulate a broad spectrum of target cells including epithelial cells, neutrophils, macrophages and T cells [3], [4], [5], [6].

Activation of the IL-6 receptor complex results in downstream signaling events in target cells including activation of the transcription factor C/EBP via the Ras-ERK-MAPK cascade. Furthermore, the transcription factor STAT-3 becomes activated via janus kinases (JAKs) leading to induction of STAT-3 target genes such as c-myc that control cell proliferation.

Section snippets

Interleukin-6 is a major regulator of T cell differentiation and activation

Functionally, IL-6 is an important factor for the synthesis of acute phase proteins such as C-reactive protein, whose serum level is increased in acute and chronic inflammatory diseases. However, recent findings clearly indicate that regulation of T cell differentiation and activation is another key field of action of IL-6. Specifically, IL-6 signaling has been found to control proliferation and resistance of resting T cells against apoptosis by inducing IL-2 production and STAT-3 activation [7]

Blockade of IL-6 signaling in collagen-induced arthritis and patients with rheumatoid arthritis

As overproduction of IL-6 has been described in rheumatoid arthritis (RA) in humans [24], [25], specific blockade of IL-6 signaling might be of interest for therapy of this disease. Animal models of RA have been utilized to address the role of IL-6 in disease pathogenesis. In the collagen-induced arthritis model (CIA), T cells are activated and produce augmented amounts of both Th1 and Th17 cytokines. Blockade of IL-6 signaling via a specific antibody (an anti-IL-6R antibody blocking both

IL-6 levels in multiple sclerosis and blockade of IL-6 signaling in experimental autoimmune encephalitis

Although no direct correlation between IL-6/sIL-6R serum levels and disease activity has been found in patients with multiple sclerosis (MS) [36], double-label immunohistochemistry demonstrated the presence of IL-6 in acute and chronic active plaques from the brain of patients with MS [37]. Interestingly, IL-6 was mainly associated with astrocytes rather than macrophages or mononuclear infiltrating cells. These findings indicated that IL-6 is predominantly located within resident glial cells in

IL-6 levels in asthma and blockade of IL-6 signaling in experimental asthma

In patients with allergic asthma, higher average plasma concentrations of IL-17 and IL-6 have been detected than in normal controls [47]. Another recent study found negative correlations between forced expiratory volume (FEV1) and sputum IL-6 levels in asthma patients indicating an inverse relationship between IL-6 levels and lung function [48]. Moreover, in a prospective study in patients with mild asthma sputum IL-6 levels were shown to correlate inversely with postbronchodilator FEV1 [49].

IL-6 levels in diabetes and blockade of IL-6 signaling in experimental models of diabetes

Conflicting data on IL-6 serum levels in autoimmune forms of diabetes have been reported. Whereas some groups reported lower levels of serum IL-6 in children with type 1 diabetes, others have found normal or even increased levels of IL-6 [58], [59], [60]. However, marked effects of prior hyperglycemia and exercise on serum levels of IL-6 were reported in children with type 1 diabetes [60] suggesting that IL-6 levels are critically dependent on physical activity and prior blood glucose levels.

Blockade of IL-6 signaling in chronic intestinal inflammation and patients with Crohn's disease

Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of inflammatory bowel disease (IBD), which are defined as chronic relapsing inflammatory diseases of the gastrointestinal tract. IBD patients with uncontrolled inflammation are at risk for development of colitis-associated colon cancer [74], [75], [76]. Importantly, proinflammatory cytokines are the main effectors in induction and perpetuation of the intestinal inflammation [8], [77], [78]. In particular, IL-6 has been

IL-6 in colitis-associated colon cancer

A recent study addressed the role of IL-6 and STAT-3 in UC patients developing colitis-associated colon cancer [98]. Patients with active UC had significantly more IL-6 and pSTAT-3-positive intestinal epithelial cells than controls with inactive disease. In high grade dysplasia and cancer, significantly more epithelial cells expressed IL-6 and activated STAT-3 compared with controls, whereas the percentage of cells expressing the STAT-3 inhibitor SOCS3 was reduced. These findings clearly

Summary and perspectives

In summary, substantial evidence has been obtained in recent years that IL-6 plays a crucial role in the pathogenesis of many chronic inflammatory and autoimmune diseases ranging from rheumatoid arthritis and multiple sclerosis to diabetes, uveoretinitis and asthma (Fig. 2) [107], [108]. Hereby, sIL-6R signaling is important for T cell effector functions and T cell survival in inflamed tissues, while mIL-6R signaling is crucial for regulatory T cell activity in vivo. Furthermore, IL-6 appears

Acknowledgement

The work of MFN and SF was supported by the German Research Council (DFG).

Markus F. Neurath is Professor of Medicine at the University of Erlangen-Nürnberg (Germany). He is head of the Department of Medicine 1 (Gastroenterology, Pulmonology, Endocrinology) at the University hospital in Erlangen. His group is mainly interested in chronic inflammatory and neoplastic diseases of the gastrointestinal tract. Special topics of interest include T cell activation, cytokine signaling as well as endoscopic imaging techniques.

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    Markus F. Neurath is Professor of Medicine at the University of Erlangen-Nürnberg (Germany). He is head of the Department of Medicine 1 (Gastroenterology, Pulmonology, Endocrinology) at the University hospital in Erlangen. His group is mainly interested in chronic inflammatory and neoplastic diseases of the gastrointestinal tract. Special topics of interest include T cell activation, cytokine signaling as well as endoscopic imaging techniques.

    Susetta Finotto is Professor at the University of Erlangen-Nürnberg (Germany). She is head of Molecular Pulmonology at the University Hospital in Erlangen. Her group is particularly interested in the pathogenesis and immunotherapy of allergic asthma as well as in the development and growth of lung cancer. Key research activities are in the fields of cytokine signaling, transcription factors and APC and T cell activation in the lung.

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