1. IL-6 pathway in the liver: From physiopathology to therapy
Dirk Schmidt-Arras, Stefan Rose-John J Hepatol. 2016 Jun;64(6):1403-15. doi: 10.1016/j.jhep.2016.02.004. Epub 2016 Feb 8.
Interleukin 6 (IL-6) is a pleiotropic four-helix-bundle cytokine that exerts multiple functions in the body. In the liver, IL-6 is an important inducer of the acute phase response and infection defense. IL-6 is furthermore crucial for hepatocyte homeostasis and is a potent hepatocyte mitogen. It is not only implicated in liver regeneration, but also in metabolic function of the liver. However, persistent activation of the IL-6 signaling pathway is detrimental to the liver and might ultimately result in the development of liver tumors. On target cells IL-6 can bind to the signal transducing subunit gp130 either in complex with the membrane-bound or with the soluble IL-6 receptor to induce intracellular signaling. In this review we describe how these different pathways are involved in the physiology and pathophyiology of the liver. We furthermore discuss how IL-6 pathways can be selectively inhibited and therapeutically exploited for the treatment of liver pathologies.
2. Principles of interleukin (IL)-6-type cytokine signalling and its regulation
Peter C Heinrich, Iris Behrmann, Serge Haan, Heike M Hermanns, Gerhard Müller-Newen, Fred Schaper Biochem J. 2003 Aug 15;374(Pt 1):1-20. doi: 10.1042/BJ20030407.
The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.
3. Historical overview of the interleukin-6 family cytokine
Sujin Kang, Masashi Narazaki, Hozaifa Metwally, Tadamitsu Kishimoto J Exp Med. 2020 May 4;217(5):e20190347. doi: 10.1084/jem.20190347.
Interleukin-6 (IL-6) has been identified as a 26-kD secreted protein that stimulates B cells to produce antibodies. Later, IL-6 was revealed to have various functions that overlap with other IL-6 family cytokines and use the common IL-6 signal transducer gp130. IL-6 stimulates cells through multiple pathways, using both membrane and soluble IL-6 receptors. As indicated by the expanding market for IL-6 inhibitors, it has become a primary therapeutic target among IL-6 family cytokines. Here, we revisit the discovery of IL-6; discuss insights regarding the roles of this family of cytokines; and highlight recent advances in our understanding of regulation of IL-6 expression.
