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The Interleukins in Health and Disease 2019
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The Interleukins in Health and Disease 2019

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (15 March 2020) | Viewed by 33791

Special Issue Editors

Prof. Dr. Tadamitsu Kishimoto

E-Mail Website
Guest Editor
Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Interests: molecular biology; immunology; IL-6; gp130; STAT3; signal transduction; tocilizumab; rheumatoid arthritis; autoimmune disease
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Masashi Narazaki

E-Mail Website
Guest Editor
Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
Interests: autoimmune disease; pathogenesis of autoimmune disease; rheumatoid arthritis, biologics; autoantibody; cytokine receptor; cytokine signal transduction; transcriptional and epigenetic regulation of cytokine genes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous special issue "The Interleukins in Health and Disease".

Interleukins continue to gather strong interest in many fields of biology, particularly in immunology and medicine. They act as soluble mediators not only on nearby cells but also on distant organs. Since the first member, IL-1, was recognized as a leukocytic pyrogen in the early 1980s, the number of interleukin family members has increased, with the most recent addition being IL-39. Interferons and TNF family members also perform as soluble mediators like interleukins. Each interleukin serves a unique physiological function in immune, hematopoietic, neuronal, and metabolic systems by mediating survival, proliferation, differentiation, and activation of various cell types. Thus, their activities are essential for harmonized ontogeny. Interleukin expression is regulated at chromatin remodeling, transcription and post-transcriptional levels. Most interleukin receptors belong to cytokine receptor family and some interleukins share receptors, thus, exhibiting biological redundancy of action. In the target cells, interleukins activate the JAK-STAT and Ras-MAPK signaling pathways to induce a set of unique genes in the respective cell types. Some interleukins, such as IL-1 and TNF family members, activate NF-kB signaling pathways to control genes involved in inflammation. These receptors and intracellular signaling pathways continue to be of significant biological interest.

Interleukins also play central roles in pathological conditions, including infectious diseases, autoimmune diseases, and malignancies. The relationship between autoimmune diseases and interleukins has led to the development of various types of interleukin inhibitors. For example, in rheumatoid arthritis, anti-TNFα antibody, anti-IL-6 receptor antibody, and JAK inhibitors have led to a paradigm shift in the therapeutic intervention in rheumatoid arthritis. Although these drugs successfully suppress already established inflammation, the mechanisms of sustained interleukin production in a pathological condition are still unclear.

This Special Issue on “the interleukins” addresses the aforementioned biological activities, production mechanisms, gene regulatory mechanisms, receptor systems, and signal transduction. Furthermore, the pathological roles of interleukins in various diseases will be assessed. We hope this Special Issue will provide a platform to allow enhanced research on this exciting topic.

Prof. Dr. Tadamitsu Kishimoto
Prof. Dr. Masashi Narazaki
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • interleukins in physiology
  • receptor system
  • signal transduction
  • gene regulation
  • interleukins in pathology
  • inflammation
  • autoimmune disease
  • inhibitor of interleukin

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Related Special Issue

Published Papers (6 papers)

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Research

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18 pages, 1897 KiB  
Article
Network between Cytokines, Cortisol and Occupational Stress in Gas and Oilfield Workers
by Marcella Reale, Erica Costantini, Chiara D’Angelo, Luca Coppeta, Rocco Mangifesta, Srinivas Jagarlapoodi, Marta Di Nicola and Luca Di Giampaolo
Int. J. Mol. Sci. 2020, 21(3), 1118; https://doi.org/10.3390/ijms21031118 - 7 Feb 2020
Cited by 12 | Viewed by 5392
Abstract
To test whether gas and oil field work is accompanied by stress and altered immune function, the perception of workplace stress, levels of salivary cortisol, plasma levels, and mononuclear cell production of cytokines were examined in 80 healthy workers recruited among a population [...] Read more.
To test whether gas and oil field work is accompanied by stress and altered immune function, the perception of workplace stress, levels of salivary cortisol, plasma levels, and mononuclear cell production of cytokines were examined in 80 healthy workers recruited among a population of operators on gas and oilfields. Specific questionnaires for determining the perception of anxiety, occupational stress, and subjective symptoms were administered. Salivary cortisol and cytokines plasma levels were evaluated by Elisa and to investigate immune function, both spontaneous and PHA- or LPS-induced expression and production of cytokines were assessed by qRT-PCR. Workers showed medium stress levels at work, with growth and increased motivation for work, and based on salivary cortisol concentrations, were divided into two groups of ≤10 ng/mL (n = 31) or >10 ng/mL (n = 49). Statistically significant higher plasma levels of IL-6, while lower TNFα, were detected in workers with cortisol >10 ng/mL. Also, BMI, DL, JD and Job strain were significantly higher in workers with cortisol >10 ng/mL. Thus, even modest variations of cortisol might have a role in the modulation of immune response and worker’s vulnerability to health imbalance.Thus, the evaluation of immune status, in addition to cortisol levels, could be useful to prevent illnesses; exacerbation of pre-existing conditions; morbidity; and consequent absences from work, with economic repercussions. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease 2019)
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9 pages, 1170 KiB  
Communication
IL-1β Induces SOCS2 Expression in Human Dendritic Cells
by Muamera Sarajlic, Theresa Neuper, Kim Tamara Föhrenbach Quiroz, Sara Michelini, Julia Vetter, Susanne Schaller and Jutta Horejs-Hoeck
Int. J. Mol. Sci. 2019, 20(23), 5931; https://doi.org/10.3390/ijms20235931 - 25 Nov 2019
Cited by 6 | Viewed by 4039
Abstract
Dendritic cells (DCs) regulate immunity and inflammation and respond to various stimuli, including cytokines. IL-1β is a key cytokine in the course of both acute and chronic inflammatory responses, making it indispensable for protection of the host, but also linking it to several [...] Read more.
Dendritic cells (DCs) regulate immunity and inflammation and respond to various stimuli, including cytokines. IL-1β is a key cytokine in the course of both acute and chronic inflammatory responses, making it indispensable for protection of the host, but also linking it to several diseases. Thus, IL-1β signaling must be tightly regulated. As suppressor of cytokine signaling (SOCS) proteins effectively control immune responses, we investigated the role of SOCS2 in IL-1β-induced DC activation. Human monocyte-derived DCs were stimulated with IL-1β, and SOCS2 mRNA and protein levels were measured. DC activation was assessed by cytokine secretion and surface marker expression. For functional analysis, small interfering RNA (siRNA)-based SOCS2 silencing was performed. SOCS2 expression was also analyzed in a curated NCBI GEO dataset of myeloid leukemia patients. We found IL-1β to be a potent inducer of SOCS2 expression. By silencing SOCS2, we showed that SOCS2 specifically limits IL-1β-induced IL-8 secretion. Moreover, our analysis revealed that SOCS2 levels are significantly increased in patients with acute and chronic myeloid leukemia, two hematological malignancies where disease progression is closely linked to IL-1β. This study identifies SOCS2 as a novel IL-1β-inducible target gene and points toward a potential role of SOCS2 in IL-1β-mediated DC activation. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease 2019)
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30 pages, 6176 KiB  
Article
Interleukin-6 Induces Myogenic Differentiation via JAK2-STAT3 Signaling in Mouse C2C12 Myoblast Cell Line and Primary Human Myoblasts
by Paul J. Steyn, Kevin Dzobo, Robert I. Smith and Kathryn H. Myburgh
Int. J. Mol. Sci. 2019, 20(21), 5273; https://doi.org/10.3390/ijms20215273 - 24 Oct 2019
Cited by 59 | Viewed by 8559
Abstract
Postnatal muscle growth and exercise- or injury-induced regeneration are facilitated by myoblasts. Myoblasts respond to a variety of proteins such as cytokines that activate various signaling cascades. Cytokines belonging to the interleukin 6 superfamily (IL-6) influence myoblasts’ proliferation but their effect on differentiation [...] Read more.
Postnatal muscle growth and exercise- or injury-induced regeneration are facilitated by myoblasts. Myoblasts respond to a variety of proteins such as cytokines that activate various signaling cascades. Cytokines belonging to the interleukin 6 superfamily (IL-6) influence myoblasts’ proliferation but their effect on differentiation is still being researched. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is one of the key signaling pathways identified to be activated by IL-6. The aim of this study was to investigate myoblast fate as well as activation of JAK-STAT pathway at different physiologically relevant IL-6 concentrations (10 pg/mL; 100 pg/mL; 10 ng/mL) in the C2C12 mouse myoblast cell line and primary human myoblasts, isolated from eight young healthy male volunteers. Myoblasts’ cell cycle progression, proliferation and differentiation in vitro were assessed. Low IL-6 concentrations facilitated cell cycle transition from the quiescence/Gap1 (G0/G1) to the synthesis (S-) phases. Low and medium IL-6 concentrations decreased the expression of myoblast determination protein 1 (MyoD) and myogenin and increased proliferating cell nuclear antigen (PCNA) expression. In contrast, high IL-6 concentration shifted a larger proportion of cells to the pro-differentiation G0/G1 phase of the cell cycle, substantiated by significant increases of both MyoD and myogenin expression and decreased PCNA expression. Low IL-6 concentration was responsible for prolonged JAK1 activation and increased suppressor of cytokine signaling 1 (SOCS1) protein expression. JAK-STAT inhibition abrogated IL-6-mediated C2C12 cell proliferation. In contrast, high IL-6 initially increased JAK1 activation but resulted in prolonged JAK2 activation and elevated SOCS3 protein expression. High IL-6 concentration decreased interleukin-6 receptor (IL-6R) expression 24 h after treatment whilst low IL-6 concentration increased IL-6 receptor (IL-6R) expression at the same time point. In conclusion, this study demonstrated that IL-6 has concentration- and time-dependent effects on both C2C12 mouse myoblasts and primary human myoblasts. Low IL-6 concentration induces proliferation whilst high IL-6 concentration induces differentiation. These effects are mediated by specific components of the JAK/STAT/SOCS pathway. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease 2019)
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17 pages, 4089 KiB  
Article
Interleukin (IL)-22 from IL-20 Subfamily of Cytokines Induces Colonic Epithelial Cell Proliferation Predominantly through ERK1/2 Pathway
by Md. Moniruzzaman, Ran Wang, Varinder Jeet, Michael A. McGuckin and Sumaira Z. Hasnain
Int. J. Mol. Sci. 2019, 20(14), 3468; https://doi.org/10.3390/ijms20143468 - 15 Jul 2019
Cited by 30 | Viewed by 5762
Abstract
The interleukin (IL)-20 subfamily of cytokines consists of IL-19, IL-20, IL-22, IL-24, and IL-26, and the expression of IL-20, IL-22, and IL-24 is reported to be higher in the colon of patients with ulcerative colitis. Although the receptors for these cytokines are highly [...] Read more.
The interleukin (IL)-20 subfamily of cytokines consists of IL-19, IL-20, IL-22, IL-24, and IL-26, and the expression of IL-20, IL-22, and IL-24 is reported to be higher in the colon of patients with ulcerative colitis. Although the receptors for these cytokines are highly expressed in the colon epithelium, their effects on epithelial renewal are not clearly understood. This study evaluated the effects of IL-20, IL-22, and IL-24 in epithelial renewal using the LS174T human colon cancer epithelial cell line. LS174T cells were treated with IL-20, IL-22, and IL-24 (25, 50, and 100 ng/mL) and a live-cell imaging system was used to evaluate the effects on cell proliferation. Following treatment, the signaling pathways contributing to cell proliferation were investigated through Western blotting in LS174T cells and downstream transcriptional changes through qRT-PCR in LS174T cells, and RNA-Seq in primary murine intestinal epithelial cells. Our results demonstrated that only IL-22 promoted LS174T cell proliferation, mediated via extracellular-signal-regulated kinase (ERK)1/2-mediated downstream regulation of p90RSK, c-Jun, and transcriptional changes of TRIM15 and STOM. IL-22 also promoted expression of ERK1/2-independent genes such as DDR2, LCN2, and LRG1, which are known to be involved in cell proliferation and migration. This study suggests that IL-22 induces cell proliferation in highly proliferative cells such as intestinal epithelial cells. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease 2019)
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14 pages, 2659 KiB  
Article
Low Expression of IL-10 in Circulating Bregs and Inverted IL-10/TNF-α Ratio in Tears of Patients with Perennial Allergic Conjunctivitis: A Preliminary Study
by Alberto Salazar, Israel Casanova-Méndez, Michele Pacheco-Quito, Henry Velázquez-Soto, Julio Ayala-Balboa, Enrique O. Graue-Hernández, Jeanet Serafín-López and María C. Jiménez-Martínez
Int. J. Mol. Sci. 2019, 20(5), 1035; https://doi.org/10.3390/ijms20051035 - 27 Feb 2019
Cited by 7 | Viewed by 4848
Abstract
Allergic conjunctivitis (AC) is one of the most common ophthalmological disorders seen in clinical practice. Growing evidence from recent years suggests that a subset of IL-10-expressing B cells is involved in inflammatory allergic diseases. In this study, we aimed to evaluate the potential [...] Read more.
Allergic conjunctivitis (AC) is one of the most common ophthalmological disorders seen in clinical practice. Growing evidence from recent years suggests that a subset of IL-10-expressing B cells is involved in inflammatory allergic diseases. In this study, we aimed to evaluate the potential involvement of blood Bregs cells in perennial allergic conjunctivitis (PAC), and interleukins (IL)-1β, IL-6, IL-8, IL-10, and IL-12, and tumor necrosis factor (TNF)-α, were measured in tear samples and compared with healthy controls (HC) using flow cytometry. Non-significant differences in CD19+IL-10+ cell frequency between PAC patients and healthy controls (HC) were observed. Nevertheless, when we analyzed the mean fluorescence intensity (MFI) of IL-10 on CD19+CD38Lo/Med/Hi-gated cells, we observed a significant decrease in MFI in all Bregs subsets in PAC patients. Additionally, tear cytokines showed 2.8 times lower levels of IL-10 than TNF-α in PAC patients when compared to HC. Our findings demonstrate an immunological dysregulation in patients with allergic conjunctivitis, characterized by the low expression of IL-10 in circulating CD19+CD38+ Bregs subsets and an inverted tear IL-10/TNF-α ratio, promoting a local pro-inflammatory microenvironment. These findings highlight the novel pathologic changes involved in ocular allergic diseases. Understanding systemic and local mechanisms will aid the design of immunomodulating therapeutics at different levels. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease 2019)
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Review

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18 pages, 1031 KiB  
Review
Cytokine Modulation in Breast Cancer Patients Undergoing Radiotherapy: A Revision of the Most Recent Studies
by Raffaella Marconi, Annalisa Serafini, Anna Giovanetti, Cecilia Bartoleschi, Maria Chiara Pardini, Gianluca Bossi and Lidia Strigari
Int. J. Mol. Sci. 2019, 20(2), 382; https://doi.org/10.3390/ijms20020382 - 17 Jan 2019
Cited by 17 | Viewed by 4671
Abstract
Breast cancer (BC) is the most common tumor and the second cause for cancer-related death in women worldwide, although combined treatments are well-established interventions. Several effects seem to be responsible for poor outcomes in advanced or triple-negative BC patients. Focusing on the interaction [...] Read more.
Breast cancer (BC) is the most common tumor and the second cause for cancer-related death in women worldwide, although combined treatments are well-established interventions. Several effects seem to be responsible for poor outcomes in advanced or triple-negative BC patients. Focusing on the interaction of ionizing radiation with tumor and normal tissues, the role of cytokine modulation as a surrogate of immunomodulation must still be explored. In this work, we carried out an overview of studies published in the last five years involving the cytokine profile in BC patients undergoing radiotherapy. The goal of this review was to evaluate the profile and modulation of major cytokines and interleukins as potential biomarkers of survival, treatment response, and toxicity in BC patient undergoing radiotherapy. Out of 47 retrieved papers selected using PubMed search, 15 fulfilled the inclusion criteria. Different studies reported that the modulation of specific cytokines was time- and treatment-dependent. Radiotherapy (RT) induces the modulation of inflammatory cytokines up to 6 months for most of the analyzed cytokines, which in some cases can persist up to several years post-treatment. The role of specific cytokines as prognostic and predictive of radiotherapy outcome is critically discussed. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease 2019)
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