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Biomedicines
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The Interleukin-6 Family in Disease Pathogenesis and Therapy
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The Interleukin-6 Family in Disease Pathogenesis and Therapy

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 50154

Special Issue Editors

Dr. Steven E. Mutsaers

E-Mail Website
Guest Editor
Institute for Respiratory Health, University of Western Australia, Perth, Australia
Interests: pulmonary fibrosis; mesothelial cell biology; malignant mesothelioma; post-operative adhesions; cell signalling; macrophage biology; animal models of disease
Special Issues, Collections and Topics in MDPI journals
Prof. Cecilia M. Prêle

E-Mail Website
Guest Editor
Institute for Respiratory Health and University of Western Australia, Perth, Australia
Interests: pulmonary fibrosis; cell signalling; matrix regulation; malignant mesothelioma; immune regulation

Special Issue Information

Dear Colleagues,

The IL-6 family is a group of closely related pleiotropic cytokines produced by a variety of cells in response to inflammatory stimuli. They are related in structure and function and include IL-6, IL-11, leukemia inhibitory factor (LIF), Oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1), cardiotrophin like cytokine (CLC), IL-27, IL-31, and neuropoietin. The actions of these cytokines are mediated through specific cell surface receptors and the shared signal transducing subunit, gp130. Subsequent signalling is mediated through a tight reciprocal regulation of either ERK-MAPK or JAK-STAT pathways, critical for the generation of physiological responses to IL6-family cytokines. Conversely, disturbance of this finely orchestrated signalling, leads to pathological responses. The IL-6 family stimulates the inflammatory and autoimmune processes in many diseases. Hence, there is a strong interest in developing agents against these molecules or their signalling pathways to treat disease. Articles (original and reviews) are being sought for a Special Issue highlighting the importance of the IL-6 family of cytokines in both health and disease and novel approaches to modulate their function.

Prof. Steven E. Mutsaers
Prof. Cecilia M. Prêle
Guest Editors

Manuscript Submission Information

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Keywords

  • IL-6 family cytokines
  • disease pathogenesis
  • signalling pathways
  • STAT3, MAPK
  • gp130
  • inflammation
  • biomarker
  • therapeutics
  • fibrosis
  • cancer
  • autoimmune disease
  • arthritis
  • neurological disease
  • asthma

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Published Papers (7 papers)

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Research

Jump to: Review

13 pages, 1480 KiB  
Article
Reduced SOCS1 Expression in Lung Fibroblasts from Patients with IPF Is Not Mediated by Promoter Methylation or Mir155
by Cecilia M. Prêle, Thomas Iosifidis, Robin J. McAnulty, David R. Pearce, Bahareh Badrian, Tylah Miles, Sarra E. Jamieson, Matthias Ernst, Philip J. Thompson, Geoffrey J. Laurent, Darryl A. Knight and Steven E. Mutsaers
Biomedicines 2021, 9(5), 498; https://doi.org/10.3390/biomedicines9050498 - 30 Apr 2021
Cited by 3 | Viewed by 2862
Abstract
The interleukin (IL)-6 family of cytokines and exaggerated signal transducer and activator of transcription (STAT)3 signaling is implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis, but the mechanisms regulating STAT3 expression and function are unknown. Suppressor of cytokine signaling (SOCS)1 and SOCS3 block STAT3, [...] Read more.
The interleukin (IL)-6 family of cytokines and exaggerated signal transducer and activator of transcription (STAT)3 signaling is implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis, but the mechanisms regulating STAT3 expression and function are unknown. Suppressor of cytokine signaling (SOCS)1 and SOCS3 block STAT3, and low SOCS1 levels have been reported in IPF fibroblasts and shown to facilitate collagen production. Fibroblasts and lung tissue from IPF patients and controls were used to examine the mechanisms underlying SOCS1 down-regulation in IPF. A significant reduction in basal SOCS1 mRNA in IPF fibroblasts was confirmed. However, there was no difference in the kinetics of activation, and methylation of SOCS1 in control and IPF lung fibroblasts was low and unaffected by 5′-aza-2′-deoxycytidine’ treatment. SOCS1 is a target of microRNA-155 and although microRNA-155 levels were increased in IPF tissue, they were reduced in IPF fibroblasts. Therefore, SOCS1 is not regulated by SOCS1 gene methylation or microRNA155 in these cells. In conclusion, we confirmed that IPF fibroblasts had lower levels of SOCS1 mRNA compared with control fibroblasts, but we were unable to determine the mechanism. Furthermore, although SOCS1 may be important in the fibrotic process, we were unable to find a significant role for SOCS1 in regulating fibroblast function. Full article
(This article belongs to the Special Issue The Interleukin-6 Family in Disease Pathogenesis and Therapy)
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20 pages, 6020 KiB  
Article
STAT3 Signalling via the IL-6ST/gp130 Cytokine Receptor Promotes Epithelial Integrity and Intestinal Barrier Function during DSS-Induced Colitis
by Lokman Pang, Jennifer Huynh, Mariah G. Alorro, Xia Li, Matthias Ernst and Ashwini L. Chand
Biomedicines 2021, 9(2), 187; https://doi.org/10.3390/biomedicines9020187 - 12 Feb 2021
Cited by 14 | Viewed by 3352
Abstract
The intestinal epithelium provides a barrier against commensal and pathogenic microorganisms. Barrier dysfunction promotes chronic inflammation, which can drive the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although the Signal Transducer and Activator of Transcription-3 (STAT3) is overexpressed in both [...] Read more.
The intestinal epithelium provides a barrier against commensal and pathogenic microorganisms. Barrier dysfunction promotes chronic inflammation, which can drive the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although the Signal Transducer and Activator of Transcription-3 (STAT3) is overexpressed in both intestinal epithelial cells and immune cells in IBD patients, the role of the interleukin (IL)-6 family of cytokines through the shared IL-6ST/gp130 receptor and its associated STAT3 signalling in intestinal barrier integrity is unclear. We therefore investigated the role of STAT3 in retaining epithelial barrier integrity using dextran sulfate sodium (DSS)-induced colitis in two genetically modified mouse models, to either reduce STAT1/3 activation in response to IL-6 family cytokines with a truncated gp130∆STAT allele (GP130∆STAT/+), or by inducing short hairpin-mediated knockdown of Stat3 (shStat3). Here, we show that mice with reduced STAT3 activity are highly susceptible to DSS-induced colitis. Mechanistically, the IL-6/gp130/STAT3 signalling cascade orchestrates intestinal barrier function by modulating cytokine secretion and promoting epithelial integrity to maintain a defence against bacteria. Our study also identifies a crucial role of STAT3 in controlling intestinal permeability through tight junction proteins. Thus, therapeutically targeting the IL-6/gp130/STAT3 signalling axis to promote barrier function may serve as a treatment strategy for IBD patients. Full article
(This article belongs to the Special Issue The Interleukin-6 Family in Disease Pathogenesis and Therapy)
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18 pages, 3292 KiB  
Article
β-Catenin Regulates Wound Healing and IL-6 Expression in Activated Human Astrocytes
by Venkata Viswanadh Edara, Shruthi Nooka, Jessica Proulx, Satomi Stacy, Anuja Ghorpade and Kathleen Borgmann
Biomedicines 2020, 8(11), 479; https://doi.org/10.3390/biomedicines8110479 - 6 Nov 2020
Cited by 16 | Viewed by 3373
Abstract
Reactive astrogliosis is prominent in most neurodegenerative disorders and is often associated with neuroinflammation. The molecular mechanisms regulating astrocyte-linked neuropathogenesis during injury, aging and human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are not fully understood. In this study, we investigated the implications of [...] Read more.
Reactive astrogliosis is prominent in most neurodegenerative disorders and is often associated with neuroinflammation. The molecular mechanisms regulating astrocyte-linked neuropathogenesis during injury, aging and human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are not fully understood. In this study, we investigated the implications of the wingless type (Wnt)/β-catenin signaling pathway in regulating astrocyte function during gliosis. First, we identified that HIV-associated inflammatory cytokines, interleukin (IL)-1β and tumor necrosis factor (TNF)-α induced mediators of the Wnt/β-catenin pathway including β-catenin and lymphoid enhancer-binding factor (LEF)-1 expression in astrocytes. Next, we investigated the regulatory role of β-catenin on primary aspects of reactive astrogliosis, including proliferation, migration and proinflammatory responses, such as IL-6. Knockdown of β-catenin impaired astrocyte proliferation and migration as shown by reduced cyclin-D1 levels, bromodeoxyuridine incorporation and wound healing. HIV-associated cytokines, IL-1β alone and in combination with TNF-α, strongly induced the expression of proinflammatory cytokines including C-C motif chemokine ligand (CCL)2, C-X-C motif chemokine ligand (CXCL)8 and IL-6; however, only IL-6 levels were regulated by β-catenin as demonstrated by knockdown and pharmacological stabilization. In this context, IL-6 levels were negatively regulated by β-catenin. To better understand this relationship, we examined the crossroads between β-catenin and nuclear factor (NF)-κB pathways. While NF-κB expression was significantly increased by IL-1β and TNF-α, NF-κB levels were not affected by β-catenin knockdown. IL-1β treatment significantly increased glycogen synthase kinase (GSK)-3β phosphorylation, which inhibits β-catenin degradation. Further, pharmacological inhibition of GSK-3β increased nuclear translocation of both β-catenin and NF-κB p65 into the nucleus in the absence of any other inflammatory stimuli. HIV+ human astrocytes show increased IL-6, β-catenin and NF-κB expression levels and are interconnected by regulatory associations during HAND. In summary, our study demonstrates that HIV-associated inflammation increases β-catenin pathway mediators to augment activated astrocyte responses including migration and proliferation, while mitigating IL-6 expression. These findings suggest that β-catenin plays an anti-inflammatory role in activated human astrocytes during neuroinflammatory pathologies, such as HAND. Full article
(This article belongs to the Special Issue The Interleukin-6 Family in Disease Pathogenesis and Therapy)
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14 pages, 1485 KiB  
Article
Javamide-II Inhibits IL-6 without Significant Impact on TNF-alpha and IL-1beta in Macrophage-Like Cells
by Jae B. Park, Renee Peters, Quynhchi Pham and Thomas T. Y. Wang
Biomedicines 2020, 8(6), 138; https://doi.org/10.3390/biomedicines8060138 - 29 May 2020
Cited by 10 | Viewed by 4309
Abstract
The main aim of this study is to find a therapeutic compound to inhibit IL-6, not TNF-alpha and IL-1beta, in macrophage-like cells, because the high-levels of IL-6 production by macrophages are reported to cause unfavorable outcomes under several disease conditions (e.g., autoimmune diseases, [...] Read more.
The main aim of this study is to find a therapeutic compound to inhibit IL-6, not TNF-alpha and IL-1beta, in macrophage-like cells, because the high-levels of IL-6 production by macrophages are reported to cause unfavorable outcomes under several disease conditions (e.g., autoimmune diseases, and acute viral infections, including COVID-19). In this study, the potential effects of javamide-II on IL-6, IL-1beta and TNF-alpha productions were determined using their ELISA kits in macrophage-like THP-1 cells. Western blots were also performed using the same cells, to determine its effects on signaling pathways (ERK, p38, JNK, c-Fos, ATF-2, c-Jun and NF-κB p65). At concentrations of 0.2–40 µM, javamide-II inhibited IL-6 production significantly in the THP-1 cells (IC50 of 0.8 µM) (P < 0.02). However, javamide-II did not inhibit IL-1beta or TNF-alpha productions much at the same concentrations. In addition, the treatment of javamide-II decreased the phosphorylation of p38 without significant effects on ERK and JNK phosphorylations in the THP-1 cells. Furthermore, the p38 inhibition, followed by the reduction of ATF-2 phosphorylation (not c-Fos, c-Jun or NF-κB p65), led to the suppression of IL-6 mRNA expression in the cells (P < 0.02). The data indicate that javamide-II may be a potent compound to inhibit IL-6 production via suppressing the p38 signal pathway, without significant effects on the productions of TNF-alpha and IL-1beta in macrophage-like THP-1 cells. Full article
(This article belongs to the Special Issue The Interleukin-6 Family in Disease Pathogenesis and Therapy)
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Review

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18 pages, 1033 KiB  
Review
The Role of IL-6 in Skin Fibrosis and Cutaneous Wound Healing
by Blair Z. Johnson, Andrew W. Stevenson, Cecilia M. Prêle, Mark W. Fear and Fiona M. Wood
Biomedicines 2020, 8(5), 101; https://doi.org/10.3390/biomedicines8050101 - 30 Apr 2020
Cited by 261 | Viewed by 18445
Abstract
The timely resolution of wound healing is critical for restoring the skin as a protective barrier. The switch from a proinflammatory to a reparative microenvironment must be tightly regulated. Interleukin (IL)-6 is a key modulator of the inflammatory and reparative process: it is [...] Read more.
The timely resolution of wound healing is critical for restoring the skin as a protective barrier. The switch from a proinflammatory to a reparative microenvironment must be tightly regulated. Interleukin (IL)-6 is a key modulator of the inflammatory and reparative process: it is involved in the differentiation, activation, and proliferation of leukocytes, endothelial cells, keratinocytes, and fibroblasts. This review examines the role of IL-6 in the healing of cutaneous wounds, and how dysregulation of IL-6 signaling can lead to either fibrosis or a failure to heal. The role of an IL-6/TGF-β feedback loop is discussed in the context of fibrogenesis, while IL-6 expression and responses in advanced age, diabetes, and obesity is outlined regarding the development of chronic wounds. Current research on therapies that modulate IL-6 is explored. Here, we consider IL-6′s diverse impact on cutaneous wound healing. Full article
(This article belongs to the Special Issue The Interleukin-6 Family in Disease Pathogenesis and Therapy)
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16 pages, 1803 KiB  
Review
Oncostatin M in the Regulation of Connective Tissue Cells and Macrophages in Pulmonary Disease
by Carl D. Richards and Fernando Botelho
Biomedicines 2019, 7(4), 95; https://doi.org/10.3390/biomedicines7040095 - 5 Dec 2019
Cited by 17 | Viewed by 6621
Abstract
Oncostatin M (OSM), as one of the gp130/IL-6 family of cytokines, interacts with receptor complexes that include the gp130 signaling molecule and OSM receptor β OSMRβ chain subunits. OSMRβ chains are expressed relatively highly across a broad array of connective tissue (CT) cells [...] Read more.
Oncostatin M (OSM), as one of the gp130/IL-6 family of cytokines, interacts with receptor complexes that include the gp130 signaling molecule and OSM receptor β OSMRβ chain subunits. OSMRβ chains are expressed relatively highly across a broad array of connective tissue (CT) cells of the lung, such as fibroblasts, smooth muscle cells, and epithelial cells, thus enabling robust responses to OSM, compared to other gp130 cytokines, in the regulation of extracellular matrix (ECM) remodeling and inflammation. OSMRβ chain expression in lung monocyte/macrophage populations is low, whereas other receptor subunits, such as that for IL-6, are present, enabling responses to IL-6. OSM is produced by macrophages and neutrophils, but not CT cells, indicating a dichotomy of OSM roles in macrophage verses CT cells in lung inflammatory disease. ECM remodeling and inflammation are components of a number of chronic lung diseases that show elevated levels of OSM. OSM-induced products of CT cells, such as MCP-1, IL-6, and PGE2 can modulate macrophage function, including the expression of OSM itself, indicating feedback loops that characterize Macrophage and CT cell interaction. Full article
(This article belongs to the Special Issue The Interleukin-6 Family in Disease Pathogenesis and Therapy)
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15 pages, 1209 KiB  
Review
Current Knowledge of IL-6 Cytokine Family Members in Acute and Chronic Kidney Disease
by Aaron L. Magno, Lakshini Y. Herat, Revathy Carnagarin, Markus P. Schlaich and Vance B. Matthews
Biomedicines 2019, 7(1), 19; https://doi.org/10.3390/biomedicines7010019 - 13 Mar 2019
Cited by 29 | Viewed by 10352
Abstract
Healthy kidneys are important for the efficient regulation of metabolism. However, there is an ever increasing population of patients suffering from both acute and chronic kidney diseases that disrupt this homeostasis. This review will explore the emerging roles that interleukin 6 (IL-6) cytokine [...] Read more.
Healthy kidneys are important for the efficient regulation of metabolism. However, there is an ever increasing population of patients suffering from both acute and chronic kidney diseases that disrupt this homeostasis. This review will explore the emerging roles that interleukin 6 (IL-6) cytokine family members play in the pathogenesis of kidney disease. The IL-6 family of cytokines are involved in a diverse range of physiological functions. In relation to kidney disease, their involvement is no less diverse. Evidence from both preclinical and clinical sources show that IL-6 cytokine family members can play either a deleterious or protective role in response to kidney disease. This appears to be dependent on the type of kidney disease in question or the specific cytokine. Current attempts to use or target IL-6 cytokine family members as therapies of kidney diseases will be highlighted throughout this review. Finally, the involvement of IL-6 cytokine family members in kidney disease will be presented in the context of three regularly overlapping conditions: obesity, hypertension and diabetes. Full article
(This article belongs to the Special Issue The Interleukin-6 Family in Disease Pathogenesis and Therapy)
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