IL-6 Trans-Signaling via the Soluble IL-6 Receptor: Importance for the Pro-Inflammatory Activities of IL-6

Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
International journal of biological sciences (Impact Factor: 4.37). 10/2012; 8(9):1237-47. DOI: 10.7150/ijbs.4989
Source: PubMed

ABSTRACT Interleukin-6 (IL-6) is a cytokine with many activities. It has functions in the regulation of the immune system and the nervous system. Furthermore, IL-6 is involved in liver regeneration and in the metabolic control of the body. On target cells, IL-6 binds to an 80 kDa IL-6 receptor (IL-6R). The complex of IL-6 and IL-6R associates with a second protein, gp130, which thereupon dimerizes and initiates intracellular signaling. Whereas gp130 is expressed on all cells, IL-6R is only present on few cells in the body including hepatocytes and some leukocytes. Cells, which do not express IL-6R cannot respond to the cytokine, since gp130 alone has no measurable affinity for IL-6. Interestingly, a soluble form of IL-6R (sIL-6R) comprising the extracellular portion of the receptor can bind IL-6 with a similar affinity as the membrane bound IL-6R. The complex of IL-6 and sIL-6R can bind to gp130 on cells, which do not express the IL-6R, and which are unresponsive to IL-6. This process has been called trans-signaling. Here I will review published evidence that IL-6 trans-signaling is pro-inflammatory whereas classic IL-6 signaling via the membrane bound IL-6R is needed for regenerative or anti-inflammatory activities of the cytokine. Furthermore, the detailed knowledge of IL-6 biology has important consequences for therapeutic strategies aimed at the blockade of the cytokine IL-6.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Interleukin 6 (IL-6) has a broad effect on cells of the immune system and those not of the immune system and often displays hormone-like characteristics that affect homeostatic processes. IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. However, the signaling cassette that controls the activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinical experience with antagonists of IL-6 has raised new questions about how and when to block this cytokine to improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate and adaptive immunity and the possible advantages of various antagonists of IL-6 and consider how the immunobiology of IL-6 may inform clinical decisions.
    Nature Immunology 04/2015; 16(5):448-457. DOI:10.1038/ni.3153 · 24.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g., C-reactive protein, and pro-inflammatory cytokines, e.g., interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here, we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways. Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g., activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, and activation of the toll-like receptor and neuroprogressive pathways. Thirdly, anti-inflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e., path and drug discovery processes, omics-based techniques, and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, immunoproteomics and metagenomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular networks, pathways, and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways.
    Molecular Neurobiology 05/2015; DOI:10.1007/s12035-015-9183-5 · 5.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There is compelling evidence that interleukin (IL)-23/IL-17 axis plays a critical role in the pathogenesis of inflammatory spondyloarthritides including ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and inflammatory bowel disease-associated arthritis. IL-17 is a family of cytokines. Of the six members of IL-17, IL-17A and IL-17F are the most closely related proinflammatory cytokines and effector molecules. A distinct subset of CD4+ T helper (Th) cells producing IL-17A and IL-17F is designated Th17 cells. Many cytokines are involved in Th17 cell differentiation and therefore are therapeutic targets. IL-6 in combination with transforming growth factor (TGF)-β mediates initiation of Th17 cell differentiation. IL-23 is not required for the initial differentiation of Th17 cells, but is indispensable for stabilizing differentiated Th17 clones in vivo. Clinical trials are undergoing to assess therapeutic efficacy of several monoclonal antibodies against these cytokines to suppress Th17 cells. Ustekinumab, a monoclonal antibody against p40 subunit which is shared by IL-12 and IL-23, has been approved to treat psoriasis and psoriatic arthritis. The therapeutic effect of ustekinumab is thought to be via inhibition of Th17 cells. Monoclonal antibodies to IL-17A and IL-17F and their receptors are also being evaluated in clinical trials. Retinoic acid-related orphan nuclear receptor (ROR)-γt is the master transcription factor for Th17 cells and hence a target. Recently, small molecules blocking ROR-γt activity have been identified and are potentially to be developed as drugs to inhibit Th17 cells. Small interfering RNA (siRNA) and small hairpin RNA (shRNA) targeting Rorc gene can be specifically delivered into CD4+ T cells to suppress IL-17 production for even more precise inhibition of Th17 cells. Technology advancement shows promise for these nucleotide-based therapeutics to be developed for clinical use.
    06/2015; 1(2). DOI:10.1007/s40674-015-0017-4

Full-text (4 Sources)

Available from
May 27, 2014