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Interleukin-6 and the Lung
Published in Jason Kelley, Cytokines of the Lung, 2022
Ralph J. Zitnik, Jack A. Elias
The demonstration that the IL-6 receptor does not contain consensus sequences specific for known signal transduction systems and does not activate the major signal transduction pathways led many to suspect that the IL-6 receptor molecule that had been cloned was only part of a larger multimeric receptor complex. Support for this contention came from studies in which it was shown that a soluble version of the IL-6 receptor, which lacked its transmembrane anchor, was capable of inducing an IL-6 stimulus in cells that did not normally express the IL-6 receptor (Yasukawa et al., 1990). There are several lines of evidence that suggest that the glycoprotein gp130 is an important component of this multimeric complex. First, all IL-6–responsive cells yet studied express gp130. Second, the MT12 cell line, which expresses gp130, but not the IL-6 receptor, shows IL-6 responsiveness in the presence of soluble IL-6 receptor. Third, transfection of MT12 cells with expression constructs containing IL-6 receptor cDNA makes them IL-6-responsive. Fourth, soluble gp130 protein interacts with the IL-6 receptor in solution only in the presence of IL-6 protein (Yasukawa et al., 1990; Taga et al., 1989).
Insulin Resistance and Glucose Regulation
Published in Awanish Kumar, Ashwini Kumar, Diabetes, 2020
Interleukin-6 (IL-6) is a cytokine produced by a variety of cells such as immune cells, endothelial cells and fibroblasts. It is a 22–27 kDa pro-inflammatory protein which binds to its transmembrane receptor gp130. Approximately 30% of IL-6 is secreted by adipocytes; thus, it has been listed as an important adipokine. Like many adipokines, IL-6 level has been positively correlated to insulin resistance and T2DM. It has been seen that weight reduction decreases the IL-6 concentration, thereby improving insulin sensitivity. Among the many mechanisms involved in developing insulin resistance, IL-6 decreases IRS-1 activation, and the PI-3 kinase is decreased while hepatic glycogenesis is also significantly reduced, indicating a hepatic insulin resistance as well. The decrease in IR and IRS-1 phosphorylation is subjected to the fact that IL-6 upregulates SOCS3 expression which in turn displays such actions. Infusion of recombinant IL-6 in animal models also resulted in elevated hepatic glucose production. It also has a marked action of increasing FFA which also augments the insulin resistance. It also partly downregulates the expression of adiponectin. TNF-α is also said to induce the expression of IL-6. An important controversy lies in the fact that IL-6 promotes FFA oxidation and promotes uptake of glucose in skeletal muscle cells [34–36], while reducing the hepatic glycogenesis and glucose uptake in adipocytes, with the mechanisms remaining unclear.
Fibroids and Endometrial Receptivity/Embryo Implantation
Published in Botros R.M.B. Rizk, Yakoub Khalaf, Mostafa A. Borahay, Fibroids and Reproduction, 2020
Kamaria C. Cayton Vaught, Maria Facadio Antero, Jacqueline Y. Maher, Chantel I. Cross
Both LIF and IL-11 act through the same gp130 signaling pathway [7,47]. Inactivation of this pathway has been associated with implantation failure in murine models [48]. Mice that are LIF deficient have recurrent implantation failure secondary to poor endometrial decidualization. Embryos from these defective mice are able to implant in wild-type mice [49]. Clinically, dysregulation of LIF expression during the secretory phase has been associated with unexplained infertility and recurrent pregnancy loss [50]. Peak LIF expression in humans coincides with the WOI. In the presence of submucosal fibroids, this increase in LIF expression is blunted [51]. Therefore, the presence of fibroids may prevent the release of cytokines, which are essential for implantation.
The safety and efficacy of interleukin 11 for radiation injury
Published in Expert Opinion on Drug Safety, 2023
Interleukin 11 (IL-11) is a member of the IL-6 family with several, well-documented modes of biological action, namely and most notably, stimulatory and maturational actions on megakaryocytopoiesis within hematopoietic tissues and related thrombocytopoiesis, along with anti-inflammatory and cytoprotective effects on both gastrointestinal (GI) crypts and hematopoietic progenitors [1]. IL-11 belongs to the gp130 family of cytokines and besides IL-6, IL-11 is the only member of this family which acts on a homodimer of the ubiquitously expressed gp130 co-receptor. Responsiveness of cells is, therefore, determined by the presence of the IL-11 receptor (the IL-6 receptor in the case of IL-6). It might be possible that certain cells are not responsive to IL-11 due to the lack of the IL-11 receptor expression. In such a case, the use of a ‘Hyper-IL-11’ (soluble IL-11 receptor-α fused with IL-11 without any artificial linker to avoid induction of antibody production) might be not only possible but perhaps appropriate [2].
The cytokine storm of COVID-19: a spotlight on prevention and protection
Published in Expert Opinion on Therapeutic Targets, 2020
Lucie Pearce, Sean M. Davidson, Derek M. Yellon
It is possible to consider IL-6 as both ‘friend and foe’; given its ability to ‘class-switch’ into either a pro- or anti-inflammatory form, as mediated by the protease TACE (TNF-α-converting enzyme). When IL-6 is bound to its soluble receptor (sIL-6 R), a cascade of hyper-inflammation is induced, whereas the IL-6-membrane bound IL-6 complex, downregulates this response [20]. IL-6 intra-cellular signaling is complex, involving the gp130 receptor, JAK/STAT, RAS/RAF and AKT/P13 K pathways [19]. The IL-6 ‘classical’ pathway involves the IL-6 receptor (IL-6 R) which binds directly to gp130. The ‘trans’ signaling pathway uses soluble sIL-6 receptors to aid gp130 binding and signal transduction in cells which do not express membrane bound IL-6 R [19]. In an animal model of influenza, IL-6 knock-out mice were found to have an increased mortality, reduced phagocytic function and increased fibroblast proliferation [22]. Therefore, the ability of IL-6 to initiate chemotaxis and immune system polarization, may make its inhibition unfavorable in the early disease course.
Local Cytokine Expression Profiling in Patients with Specific Autoimmune Uveitic Entities
Published in Ocular Immunology and Inflammation, 2020
Ahmed M. Abu El-Asrar, Nele Berghmans, Saleh A. Al-Obeidan, Priscilla W. Gikandi, Ghislain Opdenakker, Jo Van Damme, Sofie Struyf
The IL-6 family of cytokines is defined by the shared use of the glycoprotein-130 (gp130) receptor β-subunit. The engagement of the gp130 receptor induces activation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway. Included within this family are IL-6 and IL-11.24,25 Signaling by IL-11 proceeds via an interaction of the protein with its membrane-specific receptor IL-11Rα and a subsequent interaction of the complex with the transmembrane signal-transducing receptor gp130.26 Among the cytokines analyzed, IL-11 was the most strongly upregulated in AH samples from patients with autoimmune uveitis. Our analysis identified a significant positive correlation between AH levels of IL-11 and clinical disease activity. Furthermore, our subgroup analysis showed that IL-11 levels were significantly higher in patients with HLA-B27-associated uveitis than in patients with sarcoidosis and VKH disease. The levels of IL-11 were elevated 1537.9-fold in HLA-B27-associated uveitis compared to controls. Our findings suggest that IL-11 is important in the pathogenesis of HLA-B27-associated uveitis.