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

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 (30 September 2018) | Viewed by 153499

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,

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.

We still receiving manuscripts and expecting new ones, we collect manuscripts for volume 2 at the same topic "The Interleukins in Health and Disease 2019".

Prof. Dr. Tadamitsu Kishimoto
Assoc. 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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Published Papers (18 papers)

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Research

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18 pages, 3478 KiB  
Article
Recurrent Stimulation of Natural Killer Cell Clones with K562 Expressing Membrane-Bound Interleukin-21 Affects Their Phenotype, Interferon-γ Production, and Lifespan
by Maria A. Streltsova, Sofya A. Erokhina, Leonid M. Kanevskiy, Maria V. Grechikhina, Polina A. Kobyzeva, Dean A. Lee, William G. Telford, Alexander M. Sapozhnikov and Elena I. Kovalenko
Int. J. Mol. Sci. 2019, 20(2), 443; https://doi.org/10.3390/ijms20020443 - 21 Jan 2019
Cited by 15 | Viewed by 5661
Abstract
A pattern of natural killer cell (NK cell) heterogeneity determines proliferative and functional responses to activating stimuli in individuals. Obtaining the progeny of a single cell by cloning the original population is one of the ways to study NK cell heterogeneity. In this [...] Read more.
A pattern of natural killer cell (NK cell) heterogeneity determines proliferative and functional responses to activating stimuli in individuals. Obtaining the progeny of a single cell by cloning the original population is one of the ways to study NK cell heterogeneity. In this work, we sorted single cells into a plate and stimulated them via interleukin (IL)-2 and gene-modified K562 feeder cells that expressed membrane-bound IL-21 (K562-mbIL21), which led to a generation of phenotypically confirmed and functionally active NK cell clones. Next, we applied two models of clone cultivation, which differently affected their phenotype, lifespan, and functional activity. The first model, which included weekly restimulation of clones with K562-mbIL21 and IL-2, resulted in the generation of relatively short-lived (5–7 weeks) clones of highly activated NK cells. Levels of human leukocyte antigen class II molecule—DR isotype (HLA-DR) expression in the expanded NK cells correlated strongly with interferon-γ (IFN-γ) production. The second model, in which NK cells were restimulated weekly with IL-2 alone and once on the sixth week with K562-mbIL21 and IL-2, produced long-lived clones (8–14 weeks) that expanded up to 107 cells with a lower ability to produce IFN-γ. Our method is applicable for studying variability in phenotype, proliferative, and functional activity of certain NK cell progeny in response to the stimulation, which may help in selecting NK cells best suited for clinical use. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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13 pages, 4033 KiB  
Article
IL-24 Promotes Apoptosis through cAMP-Dependent PKA Pathways in Human Breast Cancer Cells
by Leah Persaud, Jason Mighty, Xuelin Zhong, Ashleigh Francis, Marifer Mendez, Hilal Muharam, Stephen M. Redenti, Dibash Das, Bertal Huseyin Aktas and Moira Sauane
Int. J. Mol. Sci. 2018, 19(11), 3561; https://doi.org/10.3390/ijms19113561 - 12 Nov 2018
Cited by 24 | Viewed by 6578
Abstract
Interleukin 24 (IL-24) is a tumor-suppressing protein, which inhibits angiogenesis and induces cancer cell-specific apoptosis. We have shown that IL-24 regulates apoptosis through phosphorylated eukaryotic initiation factor 2 alpha (eIF2α) during endoplasmic reticulum (ER) stress in cancer. Although multiple stresses converge on eIF2α [...] Read more.
Interleukin 24 (IL-24) is a tumor-suppressing protein, which inhibits angiogenesis and induces cancer cell-specific apoptosis. We have shown that IL-24 regulates apoptosis through phosphorylated eukaryotic initiation factor 2 alpha (eIF2α) during endoplasmic reticulum (ER) stress in cancer. Although multiple stresses converge on eIF2α phosphorylation, the cellular outcome is not always the same. In particular, ER stress-induced apoptosis is primarily regulated through the extent of eIF2α phosphorylation and activating transcription factor 4 (ATF4) action. Our studies show for the first time that cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activation is required for IL-24-induced cell death in a variety of breast cancer cell lines and this event increases ATF4 activity. We demonstrate an undocumented role for PKA in regulating IL-24-induced cell death, whereby PKA stimulates phosphorylation of p38 mitogen-activated protein kinase and upregulates extrinsic apoptotic factors of the Fas/FasL signaling pathway and death receptor 4 expression. We also demonstrate that phosphorylation and nuclear import of tumor suppressor TP53 occurs downstream of IL-24-mediated PKA activation. These discoveries provide the first mechanistic insights into the function of PKA as a key regulator of the extrinsic pathway, ER stress, and TP53 activation triggered by IL-24. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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31 pages, 3940 KiB  
Article
Theoretical Studies on the Engagement of Interleukin 18 in the Immuno-Inflammatory Processes Underlying Atherosclerosis
by Dorota Formanowicz, Kaja Gutowska and Piotr Formanowicz
Int. J. Mol. Sci. 2018, 19(11), 3476; https://doi.org/10.3390/ijms19113476 - 05 Nov 2018
Cited by 21 | Viewed by 4263
Abstract
Interleukin 18 (IL-18) is one of the pro-inflammatory cytokines expressed by macrophages, suggesting that it plays important physiological and immunological functions, among the others: stimulation of natural killers (NKs) and T cells to interferon gamma (IFN- γ ) synthesis. IL-18 was originally identified [...] Read more.
Interleukin 18 (IL-18) is one of the pro-inflammatory cytokines expressed by macrophages, suggesting that it plays important physiological and immunological functions, among the others: stimulation of natural killers (NKs) and T cells to interferon gamma (IFN- γ ) synthesis. IL-18 was originally identified as interferon gamma inducing factor and now it is recognized as multifunctional cytokine, which has a role in regulation of innate and adaptive immune responses. Therefore, in order to investigate IL-18 contribution to the immuno-inflammatory processes underlying atherosclerosis, a systems approach has been used in our studies. For this purpose, a model of the studied phenomenon, including selected pathways, based on the Petri-net theory, has been created and then analyzed. Two pathways of IL-18 synthesis have been distinguished: caspase 1-dependent pathway and caspase 1-independent pathway. The analysis based on t-invariants allowed for determining interesting dependencies between IL-18 and different types of macrophages: M1 are involved in positive regulation of IL-18, while M2 are involved in negative regulation of IL-18. Moreover, the obtained results showed that IL-18 is produced more often via caspase 1-independent pathway than caspase 1-dependent pathway. Furthermore, we found that this last pathway may be associated with caspase 8 action. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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10 pages, 2513 KiB  
Communication
The Potential Role of a Soluble γ-Chain Cytokine Receptor as a Regulator of IL-7-Induced Lymphoproliferative Disorders
by Geona Kim, Yuna Jo, Byunghyuk Lee, Laraib Amir Ali, Boae Lee and Changwan Hong
Int. J. Mol. Sci. 2018, 19(11), 3375; https://doi.org/10.3390/ijms19113375 - 28 Oct 2018
Cited by 2 | Viewed by 2685
Abstract
IL-7 is an essential, nonredundant growth factor for T and B cell generation and maintenance. While IL-7 deficiency results in lymphopenia, overexpression of IL-7 can cause neoplasia in experimental models. IL-7’s involvement in neoplasia has been appreciated through studies of IL-7 transgenic (Tg) [...] Read more.
IL-7 is an essential, nonredundant growth factor for T and B cell generation and maintenance. While IL-7 deficiency results in lymphopenia, overexpression of IL-7 can cause neoplasia in experimental models. IL-7’s involvement in neoplasia has been appreciated through studies of IL-7 transgenic (Tg) mice models and human lymphoma patients. Since we recently found that a soluble form of the common γ-chain (γc) cytokine receptor (sγc) antagonistically regulates IL-7 signaling, IL-7 and sγc double-Tg mice were generated to investigate the effects of sγc overexpression in IL-7-mediated lymphoproliferative disorders (LPDs). The overexpression of sγc prevents IL-7Tg-induced abnormal increase of LN cell numbers and the development of splenomegaly, resulting in striking amelioration of mortality and disease development. These results suggest that modification of γc cytokine responsiveness by sγc molecules might control various γc cytokine-associated hematologic malignancy, and also provide an alternative view to approach antitumor therapy. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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17 pages, 419 KiB  
Article
Differences in Interleukin-8 Plasma Levels between Diabetic Patients and Healthy Individuals Independently on Their Periodontal Status
by Petra Borilova Linhartova, Denisa Kavrikova, Marie Tomandlova, Hana Poskerova, Vaclav Rehka, Ladislav Dušek and Lydie Izakovicova Holla
Int. J. Mol. Sci. 2018, 19(10), 3214; https://doi.org/10.3390/ijms19103214 - 18 Oct 2018
Cited by 24 | Viewed by 3238
Abstract
Chronic periodontitis (CP) and diabetes mellitus (DM) involve several aspects of immune functions, including neutrophil activity and cytokine biology. Considering the critical function of chemokine interleukin-8 (IL-8) in the inflammatory process, the aims of this study were to determine: (i) IL-8 plasma levels; [...] Read more.
Chronic periodontitis (CP) and diabetes mellitus (DM) involve several aspects of immune functions, including neutrophil activity and cytokine biology. Considering the critical function of chemokine interleukin-8 (IL-8) in the inflammatory process, the aims of this study were to determine: (i) IL-8 plasma levels; (ii) IL-8 (−251A/T, rs4073) and its receptor 2 (CXCR2, +1208C/T, rs1126579) polymorphisms, and (iii) the presence of the selected periodontal bacteria in types 1 and 2 DM patients (T1DM and T2DM) and systemically healthy controls (HC) with known periodontal status. This case–control study comprises of 153 unrelated individuals: 36/44 patients suffering from T1DM+CP/T2DM+CP and 32/41 from HC+CP/non-periodontitis HC. Both the clinical and biochemical parameters were monitored. The genotypes were determined using qPCR, IL-8 plasma levels were measured using an ELISA kit. Subgingival bacterial colonization was analyzed with a DNA microarray detection kit. The IL-8 plasma levels differed significantly between non-periodontitis HC and T1DM+CP/T2DM+CP patients (P < 0.01). Even in HC+CP, IL-8 concentrations were significantly lower than in T1DM+CP/T2DM+CP patients (P ≤ 0.05). No significant associations between the IL-8 plasma levels and the studied IL-8 and CXCR2 polymorphisms or the occurrence of selected periodontal bacteria (P > 0.05) were found. CP does not influence the circulating IL-8 levels. Patients with T1DM+CP/T2DM+CP had higher circulating IL-8 levels than HC+CP/non-periodontitis HC. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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21 pages, 4725 KiB  
Article
ABD-Derived Protein Blockers of Human IL-17 Receptor A as Non-IgG Alternatives for Modulation of IL-17-Dependent Pro-Inflammatory Axis
by Marie Hlavničková, Milan Kuchař, Radim Osička, Lucie Vaňková, Hana Petroková, Michal Malý, Jiří Černý, Petr Arenberger and Petr Malý
Int. J. Mol. Sci. 2018, 19(10), 3089; https://doi.org/10.3390/ijms19103089 - 09 Oct 2018
Cited by 9 | Viewed by 4306
Abstract
Interleukin 17 (IL-17) and its cognate receptor A (IL-17RA) play a crucial role in Th17 cells-mediated pro-inflammatory pathway and pathogenesis of several autoimmune disorders including psoriasis. IL-17 is mainly produced by activated Th-17 helper cells upon stimulation by IL-23 and, via binding to [...] Read more.
Interleukin 17 (IL-17) and its cognate receptor A (IL-17RA) play a crucial role in Th17 cells-mediated pro-inflammatory pathway and pathogenesis of several autoimmune disorders including psoriasis. IL-17 is mainly produced by activated Th-17 helper cells upon stimulation by IL-23 and, via binding to its receptors, mediates IL-17-driven cell signaling in keratinocytes. Hyper-proliferation of keratinocytes belongs to major clinical manifestations in psoriasis. To modulate IL-17-mediated inflammatory cascade, we generated a unique collection of IL-17RA-targeting protein binders that prevent from binding of human IL-17A cytokine to its cell-surface receptor. To this goal, we used a highly complex combinatorial library derived from scaffold of albumin-binding domain (ABD) of streptococcal protein G, and ribosome display selection, to yield a collection of ABD-derived high-affinity ligands of human IL-17RA, called ARS binders. From 67 analyzed ABD variants, 7 different sequence families were identified. Representatives of these groups competed with human IL-17A for binding to recombinant IL-17RA receptor as well as to IL-17RA-Immunoglobulin G chimera, as tested in enzyme-linked immunosorbent assay (ELISA). Five ARS variants bound to IL-17RA-expressing THP-1 cells and blocked binding of human IL-17 cytokine to the cell surface, as tested by flow cytometry. Three variants exhibited high-affinity binding with a nanomolar Kd value to human keratinocyte HaCaT cells, as measured using Ligand Tracer Green Line. Upon IL-17-stimulated activation, ARS variants inhibited secretion of Gro-α (CXCL1) by normal human skin fibroblasts in vitro. Thus, we identified a novel class of inhibitory ligands that might serve as immunosuppressive IL-17RA-targeted non-IgG protein antagonists. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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14 pages, 2790 KiB  
Article
p19-Targeting ILP Protein Blockers of IL-23/Th-17 Pro-Inflammatory Axis Displayed on Engineered Bacteria of Food Origin
by Katja Škrlec, Petra Zadravec, Marie Hlavničková, Milan Kuchař, Lucie Vaňková, Hana Petroková, Lucie Křížová, Jiří Černý, Aleš Berlec and Petr Malý
Int. J. Mol. Sci. 2018, 19(7), 1933; https://doi.org/10.3390/ijms19071933 - 01 Jul 2018
Cited by 19 | Viewed by 5538
Abstract
IL-23-mediated Th-17 cell activation and stimulation of IL-17-driven pro-inflammatory axis has been associated with autoimmunity disorders such as Inflammatory Bowel Disease (IBD) or Crohn’s Disease (CD). Recently we developed a unique class of IL-23-specific protein blockers, called ILP binding proteins that inhibit binding [...] Read more.
IL-23-mediated Th-17 cell activation and stimulation of IL-17-driven pro-inflammatory axis has been associated with autoimmunity disorders such as Inflammatory Bowel Disease (IBD) or Crohn’s Disease (CD). Recently we developed a unique class of IL-23-specific protein blockers, called ILP binding proteins that inhibit binding of IL-23 to its cognate cell-surface receptor (IL-23R) and exhibit immunosuppressive effect on human primary blood leukocytes ex vivo. In this study, we aimed to generate a recombinant Lactococcus lactis strain which could serve as in vivo producer/secretor of IL-23 protein blockers into the gut. To achieve this goal, we introduced ILP030, ILP317 and ILP323 cDNA sequences into expression plasmid vector containing USP45 secretion signal, FLAG sequence consensus and LysM-containing cA surface anchor (AcmA) ensuring cell-surface peptidoglycan anchoring. We demonstrate that all ILP variants are expressed in L. lactis cells, efficiently transported and secreted from the cell and displayed on the bacterial surface. The binding function of AcmA-immobilized ILP proteins is documented by interaction with a recombinant p19 protein, alpha subunit of human IL-23, which was assembled in the form of a fusion with Thioredoxin A. ILP317 variant exhibits the best binding to the human IL-23 cytokine, as demonstrated for particular L.lactis-ILP recombinant variants by Enzyme-Linked ImmunoSorbent Assay (ELISA). We conclude that novel recombinant ILP-secreting L. lactis strains were developed that might be useful for further in vivo studies of IL-23-mediated inflammation on animal model of experimentally-induced colitis. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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11 pages, 2909 KiB  
Article
Rosiglitazone as a Modulator of TLR4 and TLR3 Signaling Pathways in Rat Primary Neurons and Astrocytes
by Dmitry V. Chistyakov, Nadezda V. Azbukina, Alexandr V. Lopachev, Ksenia N. Kulichenkova, Alina A. Astakhova and Marina G. Sergeeva
Int. J. Mol. Sci. 2018, 19(1), 113; https://doi.org/10.3390/ijms19010113 - 02 Jan 2018
Cited by 26 | Viewed by 6425
Abstract
An antidiabetic drug of the thiazolidinedione class, rosiglitazone (RG) demonstrates anti-inflammatory properties in various brain pathologies. The mechanism of RG action in brain cells is not fully known. To unravel mechanisms of RG modulation of toll-like receptor (TLR) signaling pathways, we compare primary [...] Read more.
An antidiabetic drug of the thiazolidinedione class, rosiglitazone (RG) demonstrates anti-inflammatory properties in various brain pathologies. The mechanism of RG action in brain cells is not fully known. To unravel mechanisms of RG modulation of toll-like receptor (TLR) signaling pathways, we compare primary rat neuron and astrocyte cultures stimulated with the TLR4 agonist lipopolysaccharide (LPS) and the TLR3 agonist poly I:C (PIC). Both TLR agonists induced tumor necrosis factor (TNFα) release in astrocytes, but not in neurons. Neurons and astrocytes released interleukin-10 (IL-10) and prostaglandin E2 (PGE2) in response to LPS and PIC. RG decreased TLR-stimulated TNFα release in astrocytes as well as potentiated IL-10 and PGE2 release in both astrocytes and neurons. RG induced phosphorylation of p38 and JNK MAPK (mitogen-activated protein kinase) in neurons. The results reveal new role of RG as a modulator of resolution of neuroinflammation. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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1415 KiB  
Article
Elevated Systemic IL-6 Levels in Patients with Aneurysmal Subarachnoid Hemorrhage Is an Unspecific Marker for Post-SAH Complications
by Shafqat Rasul Chaudhry, Birgit Stoffel-Wagner, Thomas Mehari Kinfe, Erdem Güresir, Hartmut Vatter, Dirk Dietrich, Alf Lamprecht and Sajjad Muhammad
Int. J. Mol. Sci. 2017, 18(12), 2580; https://doi.org/10.3390/ijms18122580 - 01 Dec 2017
Cited by 78 | Viewed by 4678
Abstract
Background: Aneurysmal subarachnoid hemorrhage (aSAH) is still a fatal and morbid disease, although bleeding aneurysms can be secured in almost all cases. Occurrence of post-SAH complications including cerebral vasospasm, delayed cerebral ischemia, hydrocephalus, epilepsy, and infections are the main determinants of clinical outcome. [...] Read more.
Background: Aneurysmal subarachnoid hemorrhage (aSAH) is still a fatal and morbid disease, although bleeding aneurysms can be secured in almost all cases. Occurrence of post-SAH complications including cerebral vasospasm, delayed cerebral ischemia, hydrocephalus, epilepsy, and infections are the main determinants of clinical outcome. Hence, it is important to search for early predictors for specific post-SAH complications to treat these complications properly. Both cellular and molecular (cytokines) inflammation play a key role after aSAH during the phase of occurrence of post-SAH complications. Interleukin-6 (IL-6) is a well-known cytokine that has been extensively analyzed in cerebrospinal fluid (CSF) of patients after aSAH, but detailed studies exploring the role of systemic IL-6 in aSAH associated complications and its impact on early clinical outcome prediction are lacking. The current study aims to analyze the systemic IL-6 levels over two weeks after bleeding and its role in post-SAH complications. Methods: We recruited 80 aSAH patients prospectively who underwent peripheral venous blood withdrawal in serum gel tubes. The blood was centrifuged to harvest the serum, which was immediately frozen at −80 °C until analysis. Serum IL-6 levels were quantified using Immulite immunoassay system. Patient records including age, gender, post-SAH complications, aneurysm treatment, and clinical outcome (modified Rankin scale and Glasgow outcome scale) were retrieved to allow different subgroup analysis. Results: Serum IL-6 levels were significantly raised after aSAH compared to healthy controls over the first two weeks after hemorrhage. Serum IL-6 levels were found to be significantly elevated in aSAH patients presenting with higher Hunt and Hess grades, increasing age, and both intraventricular and intracerebral hemorrhage. Interestingly, serum IL-6 was also significantly raised in aSAH patients who developed seizures, cerebral vasospasm (CVS), and chronic hydrocephalus. IL-6 levels were sensitive to the development of infections and showed an increase in patients who developed pneumoniae. Intriguingly, we found a delayed increase in serum IL-6 in patients developing cerebral infarction. Finally, IL-6 levels were significantly higher in patients presenting with poor clinical outcome in comparison to good clinical outcome at discharge from hospital. Conclusion: Serum IL-6 levels were elevated early after aSAH and remained high over the two weeks after initial bleeding. Serum IL-6 was elevated in different aSAH associated complications, acting as a non-specific marker for post-SAH complications and an important biomarker for clinical outcome at discharge. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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Review

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17 pages, 595 KiB  
Review
Innate Immune Modulation by GM-CSF and IL-3 in Health and Disease
by Francesco Borriello, Maria Rosaria Galdiero, Gilda Varricchi, Stefania Loffredo, Giuseppe Spadaro and Gianni Marone
Int. J. Mol. Sci. 2019, 20(4), 834; https://doi.org/10.3390/ijms20040834 - 15 Feb 2019
Cited by 52 | Viewed by 6534
Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) and inteleukin-3 (IL-3) have long been known as mediators of emergency myelopoiesis, but recent evidence has highlighted their critical role in modulating innate immune effector functions in mice and humans. This new wealth of knowledge has uncovered novel aspects [...] Read more.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) and inteleukin-3 (IL-3) have long been known as mediators of emergency myelopoiesis, but recent evidence has highlighted their critical role in modulating innate immune effector functions in mice and humans. This new wealth of knowledge has uncovered novel aspects of the pathogenesis of a range of disorders, including infectious, neoplastic, autoimmune, allergic and cardiovascular diseases. Consequently, GM-CSF and IL-3 are now being investigated as therapeutic targets for some of these disorders, and some phase I/II clinical trials are already showing promising results. There is also pre-clinical and clinical evidence that GM-CSF can be an effective immunostimulatory agent when being combined with anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) in patients with metastatic melanoma as well as in novel cancer immunotherapy approaches. Finally, GM-CSF and to a lesser extent IL-3 play a critical role in experimental models of trained immunity by acting not only on bone marrow precursors but also directly on mature myeloid cells. Altogether, characterizing GM-CSF and IL-3 as central mediators of innate immune activation is poised to open new therapeutic avenues for several immune-mediated disorders and define their potential in the context of immunotherapies. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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20 pages, 1042 KiB  
Review
Interleukin-Mediated Pendrin Transcriptional Regulation in Airway and Esophageal Epithelia
by Simone Vanoni, Giada Scantamburlo, Silvia Dossena, Markus Paulmichl and Charity Nofziger
Int. J. Mol. Sci. 2019, 20(3), 731; https://doi.org/10.3390/ijms20030731 - 09 Feb 2019
Cited by 8 | Viewed by 4083
Abstract
Pendrin (SLC26A4), a Cl−/anion exchanger, is expressed at high levels in kidney, thyroid, and inner ear epithelia, where it has an essential role in bicarbonate secretion/chloride reabsorption, iodide accumulation, and endolymph ion balance, respectively. Pendrin is expressed at lower levels in [...] Read more.
Pendrin (SLC26A4), a Cl−/anion exchanger, is expressed at high levels in kidney, thyroid, and inner ear epithelia, where it has an essential role in bicarbonate secretion/chloride reabsorption, iodide accumulation, and endolymph ion balance, respectively. Pendrin is expressed at lower levels in other tissues, such as airways and esophageal epithelia, where it is transcriptionally regulated by the inflammatory cytokines interleukin (IL)-4 and IL-13 through a signal transducer and activator of transcription 6 (STAT6)-mediated pathway. In the airway epithelium, increased pendrin expression during inflammatory diseases leads to imbalances in airway surface liquid thickness and mucin release, while, in the esophageal epithelium, dysregulated pendrin expression is supposed to impact the intracellular pH regulation system. In this review, we discuss some of the recent findings on interleukin-mediated transcriptional regulation of pendrin and how this dysregulation impacts airway and esophagus epithelial homeostasis during inflammatory diseases. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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54 pages, 2970 KiB  
Review
Interleukin-18 in Health and Disease
by Koubun Yasuda, Kenji Nakanishi and Hiroko Tsutsui
Int. J. Mol. Sci. 2019, 20(3), 649; https://doi.org/10.3390/ijms20030649 - 02 Feb 2019
Cited by 313 | Viewed by 25299
Abstract
Interleukin (IL)-18 was originally discovered as a factor that enhanced IFN-γ production from anti-CD3-stimulated Th1 cells, especially in the presence of IL-12. Upon stimulation with Ag plus IL-12, naïve T cells develop into IL-18 receptor (IL-18R) expressing Th1 cells, which increase IFN-γ production [...] Read more.
Interleukin (IL)-18 was originally discovered as a factor that enhanced IFN-γ production from anti-CD3-stimulated Th1 cells, especially in the presence of IL-12. Upon stimulation with Ag plus IL-12, naïve T cells develop into IL-18 receptor (IL-18R) expressing Th1 cells, which increase IFN-γ production in response to IL-18 stimulation. Therefore, IL-12 is a commitment factor that induces the development of Th1 cells. In contrast, IL-18 is a proinflammatory cytokine that facilitates type 1 responses. However, IL-18 without IL-12 but with IL-2, stimulates NK cells, CD4+ NKT cells, and established Th1 cells, to produce IL-3, IL-9, and IL-13. Furthermore, together with IL-3, IL-18 stimulates mast cells and basophils to produce IL-4, IL-13, and chemical mediators such as histamine. Therefore, IL-18 is a cytokine that stimulates various cell types and has pleiotropic functions. IL-18 is a member of the IL-1 family of cytokines. IL-18 demonstrates a unique function by binding to a specific receptor expressed on various types of cells. In this review article, we will focus on the unique features of IL-18 in health and disease in experimental animals and humans. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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24 pages, 1432 KiB  
Review
The Complex Interplay between Lipids, Immune System and Interleukins in Cardio-Metabolic Diseases
by Stella Bernardi, Annalisa Marcuzzi, Elisa Piscianz, Alberto Tommasini and Bruno Fabris
Int. J. Mol. Sci. 2018, 19(12), 4058; https://doi.org/10.3390/ijms19124058 - 14 Dec 2018
Cited by 41 | Viewed by 10087
Abstract
Lipids and inflammation regulate each other. Early studies on this topic focused on the systemic effects that the acute inflammatory response—and interleukins—had on lipid metabolism. Today, in the era of the obesity epidemic, whose primary complications are cardio-metabolic diseases, attention has moved to [...] Read more.
Lipids and inflammation regulate each other. Early studies on this topic focused on the systemic effects that the acute inflammatory response—and interleukins—had on lipid metabolism. Today, in the era of the obesity epidemic, whose primary complications are cardio-metabolic diseases, attention has moved to the effects that the nutritional environment and lipid derangements have on peripheral tissues, where lipotoxicity leads to organ damage through an imbalance of chronic inflammatory responses. After an overview of the effects that acute inflammation has on the systemic lipid metabolism, this review will describe the lipid-induced immune responses that take place in peripheral tissues and lead to chronic cardio-metabolic diseases. Moreover, the anti-inflammatory effects of lipid lowering drugs, as well as the possibility of using anti-inflammatory agents against cardio-metabolic diseases, will be discussed. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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16 pages, 1370 KiB  
Review
The Interleukin-17 Family of Cytokines in Breast Cancer
by Joseph Antoine Salvator Fabre, Jérôme Giustiniani, Christian Garbar, Yacine Merrouche, Frank Antonicelli and Armand Bensussan
Int. J. Mol. Sci. 2018, 19(12), 3880; https://doi.org/10.3390/ijms19123880 - 04 Dec 2018
Cited by 48 | Viewed by 6896
Abstract
Breast cancer (BC) is the most common cancer in women worldwide and remains a major cause of mortality with an expected 137,000 death this year in Europe. Standard management of metastatic BC comprises hormonotherapy, chemotherapy, and targeted therapies. Cyclin dependent kinase (CDK) and [...] Read more.
Breast cancer (BC) is the most common cancer in women worldwide and remains a major cause of mortality with an expected 137,000 death this year in Europe. Standard management of metastatic BC comprises hormonotherapy, chemotherapy, and targeted therapies. Cyclin dependent kinase (CDK) and mammalian target of rapamycin (mTOR) inhibitors have recently proved their efficiency in hormonal receptor expressing BC. Checkpoint proteins inhibition is being evaluated in phase 3 studies. Since inflammation is constantly present in cancers, research teams have focused their attention on the interleukin-17 (IL-17) family of proinflammatory cytokines. Preclinical experiments have reported both pro and antitumor effects depending on the conditions. In the present article, we review the accumulating evidences about the roles of IL-17 in BC and discuss whether this family of cytokines could be a new target in anticancer treatments. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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28 pages, 2824 KiB  
Review
The Two-Faced Cytokine IL-6 in Host Defense and Diseases
by Masashi Narazaki and Tadamitsu Kishimoto
Int. J. Mol. Sci. 2018, 19(11), 3528; https://doi.org/10.3390/ijms19113528 - 09 Nov 2018
Cited by 134 | Viewed by 16290
Abstract
Interleukein-6 (IL-6), is produced locally from infectious or injured lesions and is delivered to the whole body via the blood stream, promptly activating the host defense system to perform diverse functions. However, excessive or sustained production of IL-6 is involved in various diseases. [...] Read more.
Interleukein-6 (IL-6), is produced locally from infectious or injured lesions and is delivered to the whole body via the blood stream, promptly activating the host defense system to perform diverse functions. However, excessive or sustained production of IL-6 is involved in various diseases. In diseases, the IL-6 inhibitory strategy begins with the development of the anti-IL-6 receptor antibody, tocilizumab (TCZ). This antibody has shown remarkable effects on Castleman disease, rheumatoid arthritis and juvenile idiopathic arthritis. In 2017, TCZ was proven to work effectively against giant cell arteritis, Takayasu arteritis and cytokine releasing syndrome, initiating a new era for the treatment of these diseases. In this study, the defensive functions of IL-6 and various pathological conditions are compared. Further, the diseases of which TCZ has been approved for treatment are summarized, the updated results of increasing off-label use of TCZ for various diseases are reviewed and the conditions for which IL-6 inhibition might have a beneficial role are discussed. Given the involvement of IL-6 in many pathologies, the diseases that can be improved by IL-6 inhibition will expand. However, the important role of IL-6 in host defense should always be kept in mind in clinical practice. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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19 pages, 721 KiB  
Review
Targeting Cytokines as Evolving Treatment Strategies in Chronic Inflammatory Airway Diseases
by Jaleesa Garth, Jarrod W. Barnes and Stefanie Krick
Int. J. Mol. Sci. 2018, 19(11), 3402; https://doi.org/10.3390/ijms19113402 - 30 Oct 2018
Cited by 64 | Viewed by 7594
Abstract
Cytokines are key players in the initiation and propagation of inflammation in chronic inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis and allergic asthma. This makes them attractive targets for specific novel anti-inflammatory treatment strategies. Recently, both interleukin-1 (IL-1) and [...] Read more.
Cytokines are key players in the initiation and propagation of inflammation in chronic inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis and allergic asthma. This makes them attractive targets for specific novel anti-inflammatory treatment strategies. Recently, both interleukin-1 (IL-1) and IL-6 have been associated with negative health outcomes, mortality and a pro-inflammatory phenotype in COPD. IL-6 in COPD was shown to correlate negatively with lung function, and IL-1beta was induced by cigarette smoke in the bronchial epithelium, causing airway inflammation. Furthermore, IL-8 has been shown to be a pro-inflammatory marker in bronchiectasis, COPD and allergic asthma. Clinical trials using specific cytokine blockade therapies are currently emerging and have contributed to reduce exacerbations and steroid use in COPD. Here, we present a review of the current understanding of the roles of cytokines in the pathophysiology of chronic inflammatory airway diseases. Furthermore, outcomes of clinical trials in cytokine blockade as novel treatment strategies for selected patient populations with those diseases will be discussed. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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34 pages, 1762 KiB  
Review
Interleukin-1 Beta—A Friend or Foe in Malignancies?
by Rebekka Bent, Lorna Moll, Stephan Grabbe and Matthias Bros
Int. J. Mol. Sci. 2018, 19(8), 2155; https://doi.org/10.3390/ijms19082155 - 24 Jul 2018
Cited by 264 | Viewed by 23785
Abstract
Interleukin-1 beta (IL-1β) is induced by inflammatory signals in a broad number of immune cell types. IL-1β (and IL-18) are the only cytokines which are processed by caspase-1 after inflammasome-mediated activation. This review aims to summarize current knowledge about parameters of regulation of [...] Read more.
Interleukin-1 beta (IL-1β) is induced by inflammatory signals in a broad number of immune cell types. IL-1β (and IL-18) are the only cytokines which are processed by caspase-1 after inflammasome-mediated activation. This review aims to summarize current knowledge about parameters of regulation of IL-1β expression and its multi-facetted role in pathophysiological conditions. IL-1 signaling activates innate immune cells including antigen presenting cells, and drives polarization of CD4+ T cells towards T helper type (Th) 1 and Th17 cells. Therefore, IL-1β has been attributed a largely beneficial role in resolving acute inflammations, and by initiating adaptive anti-tumor responses. However, IL-1β generated in the course of chronic inflammation supports tumor development. Furthermore, IL-1β generated within the tumor microenvironment predominantly by tumor-infiltrating macrophages promotes tumor growth and metastasis via different mechanisms. These include the expression of IL-1 targets which promote neoangiogenesis and of soluble mediators in cancer-associated fibroblasts that evoke antiapoptotic signaling in tumor cells. Moreover, IL-1 promotes the propagation of myeloid-derived suppressor cells. Using genetic mouse models as well as agents for pharmacological inhibition of IL-1 signaling therapeutically applied for treatment of IL-1 associated autoimmune diseases indicate that IL-1β is a driver of tumor induction and development. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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20 pages, 709 KiB  
Review
Role of Damage Associated Molecular Pattern Molecules (DAMPs) in Aneurysmal Subarachnoid Hemorrhage (aSAH)
by Shafqat Rasul Chaudhry, Ahmad Hafez, Behnam Rezai Jahromi, Thomas Mehari Kinfe, Alf Lamprecht, Mika Niemelä and Sajjad Muhammad
Int. J. Mol. Sci. 2018, 19(7), 2035; https://doi.org/10.3390/ijms19072035 - 13 Jul 2018
Cited by 67 | Viewed by 7030
Abstract
Aneurysmal subarachnoid hemorrhage (aSAH) represents only a small portion of all strokes, but accounts for almost half of the deaths caused by stroke worldwide. Neurosurgical clipping and endovascular coiling can successfully obliterate the bleeding aneurysms, but ensuing complications such as cerebral vasospasm, acute [...] Read more.
Aneurysmal subarachnoid hemorrhage (aSAH) represents only a small portion of all strokes, but accounts for almost half of the deaths caused by stroke worldwide. Neurosurgical clipping and endovascular coiling can successfully obliterate the bleeding aneurysms, but ensuing complications such as cerebral vasospasm, acute and chronic hydrocephalus, seizures, cortical spreading depression, delayed ischemic neurological deficits, and delayed cerebral ischemia lead to poor clinical outcomes. The mechanisms leading to these complications are complex and poorly understood. Early brain injury resulting from transient global ischemia can release molecules that may be critical to initiate and sustain inflammatory response. Hence, the events during early brain injury can influence the occurrence of delayed brain injury. Since the damage associated molecular pattern molecules (DAMPs) might be the initiators of inflammation in the pathophysiology of aSAH, so the aim of this review is to highlight their role in the context of aSAH from diagnostic, prognostic, therapeutic, and drug therapy monitoring perspectives. DAMPs represent a diverse and a heterogenous group of molecules derived from different compartments of cells upon injury. Here, we have reviewed the most important DAMPs molecules including high mobility group box-1 (HMGB1), S100B, hemoglobin and its derivatives, extracellular matrix components, IL-1α, IL-33, and mitochondrial DNA in the context of aSAH and their role in post-aSAH complications and clinical outcome after aSAH. Full article
(This article belongs to the Special Issue The Interleukins in Health and Disease)
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