IL-1 Cytokine Family Research Articles

Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways.

Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion of IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase-1 to generate GSDMD macropores that mediate IL-1β efflux and progression to pyroptotic lysis. Neutrophils, which rapidly accumulate in large numbers at sites of tissue infection or damage, become the predominant local source of IL-1β in coordination with their potent microbiocidal capacity. Similar to macrophages, neutrophils express GSDMD and utilize the same spectrum of diverse inflammasome platforms for caspase-1-mediated cleavage of GSDMD. Distinct from macrophages, neutrophils possess a remarkable capacity to resist progression to GSDMD-dependent pyroptotic lysis to preserve their viability for efficient microbial killing while maintaining GSDMD-dependent mechanisms for export of bioactive IL-1β. Rather, neutrophils employ cell-specific mechanisms to conditionally engage GSDMD-mediated pyroptosis in response to bacterial pathogens that use neutrophils as replicative niches. GSDMD and pyroptosis have also been mechanistically linked to induction of NETosis, a signature neutrophil pathway that expels decondensed nuclear DNA into extracellular compartments for immobilization and killing of microbial pathogens. This review summarizes a rapidly growing number of recent studies that have produced new insights, unexpected mechanistic nuances, and some controversies regarding the regulation of, and roles for, neutrophil inflammasomes, pyroptosis, and GSDMs in diverse innate immune responses.

The IL-12 family cytokines in fish: Molecular structure, expression profile and function

Interleukin (IL)-12 family cytokines including IL-12, IL-23, IL-27, IL-35 and IL-39 are heterodimeric cytokines composed of two subunits, an α-chain (entitled p35, p19 and p28) and a β-chain (namely p40 and Epstein-Barr virus-induced gene 3, EBI3). Unlike in mammals, specific whole genome duplication events in fish may generate more paralogues of these subunits as the components of IL-12 family cytokines. Although all subunit genes of IL-12 family have been isolated and identified in various fish species, some important issues on fish IL-12 family are needed to be addressed compared to the extensive study in mammals: Whether the expansion of these subunit genes results in the generation of multiple isoforms of the family cytokines; Whether the related receptor genes have similar complex repertoire corresponding to their ligands; How about the expression kinetics of these subunit paralogues particularly under the circumstance of pathogen infection and immune stimulation; How about the functional properties of IL-12 family in fish. In the past ten years, these concerns have received increasing attentions to establish the biological significance of this family cytokines in fish immunity. In this review, we summarized the current understanding of IL-12 family with a special focus on the molecular structures, inducible expression profiles and functions of IL-12 family members in fish.

The Correlation between Interleukin 33 and Psoriasis: A Systematic Review and Meta-Analysis

Psoriasis is a common genetic autoimmune disorder with a global prevalence of 2–3%. The clear pathogenesis of psoriasis is not fully understood, but hyperproliferation and inflammation of the epidermis with marked infiltration of immune cells have been indicated in psoriasis with such cells producing different types of cytokines- interleukin. As such a new member of the IL-1 cytokine family, in some research, IL-33 has been linked with psoriasis showing high serum concentration of IL-33 in human psoriatic plaques compared to normal healthy skin. Despite this, the association between IL-33 and psoriasis is not clear. Herein, in this review, we aim to investigate the correlation between serum IL-33 levels and psoriasis. We conducted meta-analysis using fixed or random-effects models to calculate pooled standard mean differences. We found that the mean IL-33 serum levels were reported between 0.35 pg/mL to 586 pg/mL in the psoriatic group and 0 pg/mL to 87.7 pg/mL in the healthy control group. Out of five, four individual studies included in the analysis reported statistically significant differences in IL-33 levels, the pooled estimate (SMD = 0.340 95% CI: −0.308 to 0.988), however, did not indicate a significant relation between IL-33 and psoriasis. This analysis revealed no significant difference between serum IL-33 levels in the psoriatic population in comparison to healthy controls. This may be because we did not include any animal studies, lab-based studies, any other markers mixed together, or any other cases of diseases mixed together. However, further research is warranted to confirm the reported association as this analysis is limited by the low-quality and observational nature of the included studies.

STAT3 is Activated by CTGF-mediated Tumor-stroma Cross Talk to Promote HCC Progression.

Signal transducer and activator of transcription 3 (STAT3) is known as a pro-oncogenic transcription factor. Regarding liver carcinogenesis, however, it remains controversial whether activated STAT3 is pro- or anti-tumorigenic. This study aimed to clarify the significance and mechanism of STAT3 activation in hepatocellular carcinoma (HCC). Hepatocyte-specific Kras-mutant mice (Alb-Cre KrasLSL-G12D/+; KrasG12D mice) were used as a liver cancer model. Cell lines of hepatoma and stromal cells including stellate cells, macrophages, T cells, and endothelial cells were used for culture. Surgically resected 12 HCCs were used for human analysis. Tumors in KrasG12D mice showed up-regulation of phosphorylated STAT3 (p-STAT3), together with interleukin (IL)-6 family cytokines, STAT3 target genes, and connective tissue growth factor (CTGF). Hepatocyte-specific STAT3 knockout (Alb-Cre KrasLSL-G12D/+ STAT3fl/fl) downregulated p-STAT3 and CTGF and suppressed tumor progression. In coculture with stromal cells, proliferation, and expression of p-STAT3 and CTGF, were enhanced in hepatoma cells via gp130/STAT3 signaling. Meanwhile, hepatoma cells produced CTGF to stimulate integrin/nuclear factor kappa B signaling and up-regulate IL-6 family cytokines from stromal cells, which could in turn activate gp130/STAT3 signaling in hepatoma cells. In KrasG12D mice, hepatocyte-specific CTGF knockout (Alb-Cre KrasLSL-G12D/+ CTGFfl/fl) downregulated p-STAT3, CTGF, and IL-6 family cytokines, and suppressed tumor progression. In human HCC, single cell RNA sequence showed CTGF and IL-6 family cytokine expression in tumor cells and stromal cells, respectively. CTGF expression was positively correlated with that of IL-6 family cytokines and STAT3 target genes in The Cancer Genome Atlas. STAT3 is activated by CTGF-mediated tumor-stroma crosstalk to promote HCC progression. STAT3-CTGF positive feedback loop could be a therapeutic target.

Association between IL-38 and inflammatory indicators in patients with bacterial pneumonia.

IL-38, a recently discovered cytokine of IL-1 family, exerts immunoregulatory activities in multi-type inflammatory diseases. However, its expression level and underlying clinical importance for IL-38 in respiratory bacterial infections remain unknown. Thirty-five patients with bacterial pneumonia and twenty age- and gender- matched healthy individuals were enrolled in the study to determine serum IL-38 concentrations by ELISA. Then, the correlation between serum IL-38 levels and clinical features were analyzed and ROC curve was used to evaluate the potential diagnostic value for bacterial infections. In vitro, LPS-stimulated human respiratory epithelial cell model was employed to explore immunomodulatory mechanism of IL-38 in pulmonary infections. Elevated serum levels of IL-38 were determined in patients with bacterial pneumonia when compared with healthy controls. In addition, serum IL-38 levels were negatively correlated with clinical inflammation parameters, including WBC count, CRP, PCT and proinflammatory IL-6 and IL-8. In vitro, we demonstrated that recombinant IL-38 was able to remarkably inhibit expression of proinflammatory IL-6, IL-8, IL-1β and TNF-α as well as adhesion molecule ICAM-1, which were partially mediated by attenuated activation of STAT3 and NF-κB signal cascades in BEAS-2B cells. Furthermore, we identified the diagnostic efficiency of IL-38 in discriminating patients with bacterial pneumonia from healthy individuals. Our study indicates higher serum IL-38 levels in patients with bacterial pneumonia are involved in anti-inflammatory activities in respiratory infections revealing a critical role of IL-38 in attenuating excessive pulmonary inflammation against exogenous pathogens. More importantly, IL-38 exhibited a potential novel biomarker for bacterial pneumonia. Thus, our data may provide useful insights for both clinical and basic research for bacterial pneumonia diagnosis.

Vasculitis Activity-Predicting Ability of IL-12 Family Cytokines in Patients with Microscopic Polyangiitis and Granulomatosis with Polyangiitis.

The present study investigated and compared the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) activity-predicting ability of the serum concentrations of the four interleukin (IL)-12 family cytokines including IL-23, IL-27, IL-35, and IL-39 in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). The present study included 70 patients with MPA and GPA. Clinical and laboratory data, particularly Birmingham Vasculitis Activity Score (BVAS), at the time of blood collection were obtained. The serum concentrations of IL-23, IL-27, IL-35, and IL-37 were measured using sera stored at -80℃. Patients were divided into two groups: the upper half of BVAS (BVAS ≥12) and the lower half of BVAS (BVAS <12). The serum concentrations of IL-23 and IL-27 reflected AAV activity. Patients with the upper half of BVAS exhibited significantly higher serum concentrations of IL-23 and IL-27 than those without. Patients with the serum concentrations of IL-23 ≥132.1 pg/mL or IL-27 ≥684.7 pg/mL exhibited higher frequency and risk for the upper half of BVAS than those without [relative risks (RR) 5.143 and RR 4.091, respectively]. The serum concentrations of IL-27 were associated with age ≥65 years and proteinase 3-ANCA (or C-ANCA) negativity, whereas, those of IL-23 were associated with MPA. However, the serum concentrations of IL-35 and IL-39 were not useful in predicting AAV activity in this study. The present study is the first to demonstrate that among the various members of IL-12 family cytokines, the serum concentrations of IL-23 and IL-27 possess AAV activity-predicting ability.

Methods to Activate the NLRP3 Inflammasome.

The inflammasome-nucleating cytoplasmic sensor protein NLRP3 (NACHT-, LRR, and PYD domains-containing protein 3, also known as NOD-like receptor pyrin domain-containing 3, NALP3, or cryopyrin) is triggered by a broad spectrum of sterile endogenous danger signals and environmental irritants. Upon activation, NLRP3 engages the adapter protein ASC that in turn recruits the third inflammasome component, the protease caspase-1. Subsequent caspase-1 activation leads to its auto-processing and maturation of the leaderless IL-1 family cytokines IL-1β and IL-18 as well as cleavage of the pore-forming protein Gasdermin D (GSDMD). GSDMD plasma membrane pores, formed by its N-terminus, facilitate IL-1 release and, typically, subsequent cell lysis (pyroptosis). This protocol explains standard methods, which are routinely used in our laboratory to study NLRP3 inflammasome biology in vitro. It includes experimental approaches using primary murine bone marrow-derived macrophages (BMDMs) and bone marrow-derived dendritic cells (BMDCs), human peripheral blood mononuclear cells (PBMCs), as well as inflammasome-competent cell lines (HoxB8 and THP-1 cells). The protocol covers the use of a broad spectrum of established NLRP3 activators and outlines the use of common inhibitors blocking NLRP3 itself or its upstream triggering events. We also provide guidelines for experimental set-up and crucial experimental controls to investigate NLRP3 inflammasome signaling or study new activators and inhibitors.

The Emerging Role of Interleukin-(IL)-11/IL-11R in Bone Metabolism and Homeostasis: From Cytokine to Osteokine.

Interleukin-(IL)-11 is a cytokine involved in hematopoiesis, cancer metastasis, and inflammation. IL-11 belongs to the IL-6 cytokine family, binding to the complex of receptors glycoprotein gp130 and the ligand-specific-receptor subunits (IL-11Rα or their soluble counterpart sIL-11R). IL-11/IL-11R signaling enhances osteoblast differentiation and bone formation and mitigates osteoclast-induced bone resorption and cancer bone metastasis. Recent studies have shown that systemic and osteoblast/osteocyte-specific IL-11 deficiency leads to reduced bone mass and formation, but also adiposity, glucose intolerance, and insulin resistance. In humans, mutations of IL-11 and the receptor IL-11RA genes are associated with height reduction, osteoarthritis, and craniosynostosis. In this review, we describe the emerging role of IL-11/IL-11R signaling in bone metabolism by targeting osteoblasts, osteoclasts, osteocytes, and bone mineralization. Furthermore, IL-11 promotes osteogenesis and suppresses adipogenesis, thereby influencing the fate of osteoblast/adipocyte differentiation derived from pluripotent mesenchymal stem cells. We have newly identified IL-11 as a bone-derived cytokine that regulates bone metabolism and the link between bone and other organs. Thus, IL-11 is vital in bone homeostasis and could be considered a potential therapeutic strategy.

STAT3 signaling induced by the IL-6 family of cytokines modulates angiogenesis.

Aberrant angiogenesis is a hallmark of cardiovascular and retinal neovascular disease. The STAT3 signaling pathway represents a potential pharmacological target for these diseases due to its impact on angiogenesis. Surprisingly, some STAT3 activators, such as the IL-6 cytokine family member oncostatin M (OSM), enhance angiogenesis, whereas others, such as ciliary neurotropic factor (CNTF), reduce it. This study aimed to clarify these conflicting effects. In contrast to the anti-angiogenic cytokine CNTF, the pro-angiogenic cytokine OSM was able to activate intracellular signaling pathways beyond the STAT3 pathway, including the ERK and AKT pathways. These differences translated into transcriptomic and metabolic shifts. siRNA-mediated STAT3 knockdown experiments showed a decrease in VEGF-induced endothelial migration and sprouting, enhancing the pro-angiogenic drive of OSM and switching the CNTF response from anti-angiogenic to pro-angiogenic. These effects correlated with a transcriptomic shift representing enhanced STAT1 and ERK activity following STAT3 knockdown, including a compensatory prolonged phosphorylated STAT1 activity. In conclusion, the angiogenic effect of STAT3 appears to be determined by cytokine-induced STAT3 specificity and simultaneous activity of other intracellular signaling pathways, whereas the STAT3 pathway, predominantly recognized for its pro-angiogenic phenotypes, reveals novel anti-angiogenic potential.

Aberrant Expression and Prognostic Potential of IL-37 in Human Lung Adenocarcinoma.

Interleukin-37 (IL-37) is a relatively new IL-1 family cytokine that, due to its immunoregulatory properties, has lately gained increasing attention in basic and translational biomedical research. Emerging evidence supports the implication of this protein in any human disorder in which immune homeostasis is compromised, including cancer. The aim of this study was to explore the prognostic and/or diagnostic potential of IL-37 and its receptor SIGIRR (single immunoglobulin IL-1-related receptor) in human tumors. We utilized a series of bioinformatics tools and -omics datasets to unravel possible associations of IL-37 and SIGIRR expression levels and genetic aberrations with tumor development, histopathological parameters, distribution of tumor-infiltrating immune cells, and survival rates of patients. Our data revealed that amongst the 17 human malignancies investigated, IL-37 exhibits higher expression levels in tumors of lung adenocarcinoma (LUAD). Moreover, the expression profiles of IL-37 and SIGIRR are associated with LUAD development and tumor stage, whereas their high mRNA levels are favorable prognostic factors for the overall survival of patients. What is more, IL-37 correlates positively with a LUAD-associated transcriptomic signature, and its nucleotide changes and expression levels are linked with distinct infiltration patterns of certain cell subsets known to control LUAD anti-tumor immune responses. Our data indicate the potential value of IL-37 and its receptor SIGIRR to serve as biomarkers and/or immune-checkpoint therapeutic targets for LUAD patients. Further, the data highlight the urgent need for further exploration of this cytokine and the underlying pathogenetic mechanisms to fully elucidate its implication in LUAD development and progression.

Determining distinct roles of IL-1α through generation of an IL-1α knockout mouse with no defect in IL-1β expression.

Interleukin 1α (IL-1α) and IL-1β are the founding members of the IL-1 cytokine family, and these innate immune inflammatory mediators are critically important in health and disease. Early studies on these molecules suggested that their expression was interdependent, with an initial genetic model of IL-1α depletion, the IL-1α KO mouse (Il1a-KOline1), showing reduced IL-1β expression. However, studies using this line in models of infection and inflammation resulted in contrasting observations. To overcome the limitations of this genetic model, we have generated and characterized a new line of IL-1α KO mice (Il1a-KOline2) using CRISPR-Cas9 technology. In contrast to cells from Il1a-KOline1, where IL-1β expression was drastically reduced, bone marrow-derived macrophages (BMDMs) from Il1a-KOline2 mice showed normal induction and activation of IL-1β. Additionally, Il1a-KOline2 BMDMs showed normal inflammasome activation and IL-1β expression in response to multiple innate immune triggers, including both pathogen-associated molecular patterns and pathogens. Moreover, using Il1a-KOline2 cells, we confirmed that IL-1α, independent of IL-1β, is critical for the expression of the neutrophil chemoattractant KC/CXCL1. Overall, we report the generation of a new line of IL-1α KO mice and confirm functions for IL-1α independent of IL-1β. Future studies on the unique functions of IL-1α and IL-1β using these mice will be critical to identify new roles for these molecules in health and disease and develop therapeutic strategies.

Protective effect of leukemia inhibitory factor on the retinal injury induced by acute ocular hypertension in rats.

Glaucoma is one of the leading causes of irreversible blindness worldwide. As such, neuroprotective therapy is essential for the treatment of this disease. Leukemia inhibitory factor (LIF) is a member of the IL-6 cytokine family and the LIF signaling pathway is considered to be one of the major endogenous factors mediating neuroprotection in the retina. Therefore, the present study aimed to investigate the possible effects of LIF in acute ocular hypertension (AOH). The intraocular pressure in rat eyes was raised to 110 mmHg for 1 h by infusing the anterior chamber with normal saline to establish the AOH model. In the treatment group, LIF was then injected into the vitreous cavity after AOH was ceased. The retinal tissues were obtained after the termination of AOH, and H&E staining was conducted to assess the morphological damage. The number of retinal ganglion cells (RGCs) was counted using the Fluoro-Gold retrograde staining method. TUNEL staining was used to determine the extent of apoptosis among the retinal cells. In addition, the protein expression levels of cleaved caspase-3, poly (ADP-ribose) polymerase (PARP), STAT3 and components of the AKT/mTOR/70-kDa ribosomal protein S6 kinase (p70S6K) signaling pathway were examined by western blotting. The results showed that AOH induced tissue swelling and structural damage in the retina, which were reversed by LIF injection. In the LIF treatment group, RGC loss was significantly inhibited and the quantity of TUNEL-stained cells was also significantly reduced, whereas the expression of cleaved caspase-3 and PARP was decreased. Furthermore, increased phosphorylation of STAT3, AKT, mTOR and p70S6K was observed after LIF treatment. By contrast, pretreatment with the STAT3 inhibitor C188-9 or the PI3K/AKT/mTOR inhibitor LY3023414 reversed the LIF-induced inhibition of RGC loss. These results suggested that exogenous LIF treatment inhibited the retinal damage induced by AOH, which was associated with the activation of STAT3 and mTOR/p70S6K signaling. Therefore, LIF may serve a role in neuroprotection for glaucoma treatment.

319 S. aureus can induce NLRP1 inflammasome activation in patients with atopic dermatitis

Inflammasome activation is needed for the production of IL-1 family cytokines IL-1β and IL-18. Both these cytokines have been suggested to influence inflammatory responses in AD, as well as genetic association of AD with polymorphisms in the IL18R1 and IL18RAP genes has been proposed. In this study, we report the increased expression of inflammasome sensor NACHT, LRR, and PYD domains-containing protein 1 (NLRP1) and adapter PYD and CARD Domain Containing (PYCARD), as well as mRNA levels of IL1B and IL18 in lesional skin of AD patients.

The immunoregulatory role of IL-35 in patients with interstitial lung disease.

Pulmonary fibrosis involves various types of immune cells and soluble mediators, including TGF-β and IL-35, a recently identified heterodimeric cytokine that belongs to the IL-12 cytokine family. However, the effect of regulatory IL-35 may play an important role in fibrotic diseases. The aim of this paper is to explore the immunoregulatory role of IL-35 in the development of fibrosis in interstitial lung disease (ILD). To gain a better understanding of this issue, the concentrations of IL-35 and different profibrotic cytokines in fibrotic (F-ILD) and non-fibrotic (NF-ILD) patients by ELISA were compared to that of intracellular IL-35 and IL-17 on CD4+ T cells stimulated in the presence of BAL or with different ratios of recombinant IL-35 (rIL-35) and TGF-β (rTGF-β), which were evaluated by flow cytometry. We observed that BAL concentration of IL-35 was lower in F patients (p < 0.001) and was negatively correlated with concentrations of TGF-β (p < 0.001) and IL-17 (p < 0.001). In supplemented cell cultures, BAL from NF but not F patients enhanced the percentage of IL-35 + CD4+ T (p < 0.001) cells and decreased the percentage of IL-17 + CD4+ T cells (p < 0.001). The percentage of IL-35 + CD4+ T cells correlated positively with BAL concentration of IL-35 (p=0.02), but correlated negatively with BAL concentrations of IL-17 (p=0.007) and TGF-β (p=0.01). After adjusting the concentrations of recombinant cytokines to establish a TGF-β: IL-35 ratio of 1:4, an enhanced percentage of IL-35 + CD4+ T cells (p < 0.001) but a decreased percentage of IL-17 + CD4+ T cells (p < 0.001) was observed. After adding recombinant IL-35 to the BAL from F patients until a 1:4 ratio of TGF-β: IL-35 was reached, a significantly increased percentage of IL-35 + CD4+ T cells (p < 0.001) and a decreased percentage of IL-17 + CD4+ T cells (p=0.003) was found. These results suggest that IL-35 may induce an anti-fibrotic response, regulating the effect of TGF-β and the inflammatory response on CD4+ T cells. In addition, the TGF-β: IL-35 ratio in BAL has been shown to be a potential biomarker to predict the outcome of F patients with ILD.

Pro- and anti-inflammatory roles of interleukin (IL)-33, IL-36, and IL-38 in inflammatory bowel disease.

Interleukin-33 (IL-33), IL-36, and IL-38 are members of the IL-1 cytokine family. The expression of each cytokine has been reported to be increased in the inflamed mucosa of patients with inflammatory bowel disease (IBD). IL-33 and IL-36 have been studied for pro- and anti-inflammatory functions, and IL-38 has been characterized as an anti-inflammatory cytokine by antagonizing the IL-36 receptor (IL-36R). IL-33 is a nuclear cytokine constitutively expressed by certain cell types such as epithelial, endothelial, and fibroblast-like cells and released on necrotic cell death. IL-33 mainly induces type 2 immune response through its receptor suppression tumorigenicity 2 (ST2) from Th2 cells and type 2 innate lymphoid cells (ILC2s), but also by stimulating Th1 cells, regulatory T cells, and CD8+ T cells. IL-36 cytokines consist of three agonists: IL-36α, IL-36β, and IL-36γ, and two receptor antagonists: IL-36R antagonist (IL-36Ra) and IL-38. All IL-36 cytokines bind to the IL-36R complex and exert various functions through NF-κB and mitogen-activated protein kinase (MAPK) pathways in inflammatory settings. IL-33 and IL-36 also play a crucial role in intestinal fibrosis characteristic manifestation of CD. In this review, we focused on the current understanding of the pro- and anti-inflammatory roles of IL-33, IL-36, and IL38 in experimental colitis and IBD patients.

Ex vivo cytokine production in psoriatic disease: Towards specific signatures in cutaneous psoriasis and peripheral psoriatic arthritis.

Psoriatic arthritis (PsA) and cutaneous psoriasis (PsO) are different phenotypes of psoriatic disease (PsD), whose underlying specific mechanisms remain incompletely understood. As cytokines are key elements to induce and tune up immune responses to drive inflammatory diseases, our objective was to assess whether clinical features, disease phenotype and PsA and PsO activity were associated with a particular ex vivo cytokine production profile. Forty-eight patients (37 PsA and 11 PsO) and 11 healthy subjects (HS) were studied. Cytokine production by peripheral blood mononuclear cells (PBMC) that were either unstimulated, or stimulated with LPS or anti-CD3/CD28 antibodies, were analysed by multiplex assay in the culture supernatants. Cytokine signature of PsD includes a high level of TNFα in supernatants of LPS-stimulated PBMC, higher levels of IL-6 and lower levels of IFN-γ and IL-17A after CD3-CD28 stimulation, as well as higher spontaneous IL-1RA and TNFα production compared to HS. High body mass index (BMI) was associated with lower levels of IL-1β, and metabolic syndrome with lower levels of IFN-γ after LPS stimulation. In PsD, dermatological activity was related with higher IL-17A level, while rheumatic activity was linked with lower levels of IFN-γ and TNFα. Comparing each PsD subtype to HS, IL-1β and IL-6 productions are higher when using LPS stimulation in PsO patients with higher levels of IL-1β and IL-1α in peripheral PsA patients after CD3/CD28 stimulation. LPS stimulation induced high levels of IL-17A in peripheral PsA compared to axial PsA. PsA patients with axial PsA share some features with PsO but shows a distinct cytokine pattern compared to peripheral PsA. PsO and the different PsA subtypes exhibit distinct ex vivo cytokine production profiles and common features of the so-called PsD. Analysis of IL-1 cytokine family and IL-6 seems to be of particular interest to distinguish PsO and peripheral PsA since it depends on monocytes in PsO and T-lymphocytes in peripheral PsA. Peripheral cytokine profiles are influenced by rheumatic and dermatological activity of the disease, and also by metabolic syndrome features. Our results highlight the crucial role of immune cell interactions with different patterns of interaction depending on clinical phenotype.

The importance of the IL-1 family of cytokines in nanoimmunosafety and nanotoxicology.

Engineered nanomaterials (ENMs) to which humans are exposed intentionally as nanomedicines or unintentionally as invaders, may elicit unforeseen immune reactions. An uncontrollable ENM-induced immune response poses a potential danger to the human body. During an immunological reaction, interleukin (IL)-1 family cytokines, which play key roles under both physiological and pathological conditions, can be secreted by various types of cells into the surrounding environment to induce a series of defensive reactions. However, the crucial roles played by IL-1 family cytokines in ENM-induced immunological responses have not attracted enough attention from researchers to date. In this review, ENM-mediated inflammatory responses and immunotoxicity are discussed, with the main focus directed to IL-1 family cytokines, including IL-1α, IL-1β, IL-1Ra, IL-18, IL-33, IL-36, IL-37, and IL-38. The potential molecular mechanisms of IL-1 family cytokine activity triggered by ENMs, particularly the activation of IL-1α, IL-1β, IL-18, and IL-33, are also reviewed. The understanding of IL-1 family cytokines on nanoimmunosafety provides a fundamental basis for designing safe ENMs that can potentially be used for nanomedicine. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

Interleukin-11 (IL11) inhibits myogenic differentiation of C2C12 cells through activation of extracellular signal-regulated kinase (ERK)

Cancer-associated cachexia (CAC) is a multifactorial wasting syndrome characterized by loss of skeletal muscle. Interleukin-11 (IL11), one of the IL6 family cytokines, is highly expressed in various types of cancer including cancers frequently associated with cachexia. However, the impact of IL11 on muscle metabolism remains to be determined. Since one of the mechanisms of muscle wasting in cachexia is defective muscle regeneration due to impaired myogenic differentiation, we examined the effect of IL11 on the differentiation of C2C12 mouse myoblasts. Treatment of C2C12 cells with recombinant mouse IL11 resulted in decreased myotube formation. In addition, IL11 treatment reduced the protein and mRNA levels of myosin heavy chain (MHC), a marker of myogenic differentiation. Moreover, the levels of myogenic regulatory factors including myogenin and Mrf4 were significantly reduced by IL11 treatment. IL11 treatment increased the number of BrdU-positive cells and the level of phosphorylated retinoblastoma (Rb) protein, while the levels of p21Waf1 and p27Kip1 were reduced by IL11 treatment in differentiating C2C12 cells, suggesting that IL11 interferes with cell cycle exit during the early stages of myogenic differentiation. Consistent with this, IL11 treatment at the late stage of differentiation did not affect myotube formation and MHC expression. IL11 treatment resulted in an activation of ERK, STAT3, and AKT in differentiating C2C12 cells. However, only ERK inhibitors including PD98059 and U0126 were able to ameliorate the suppressive effect of IL11 on the expression of MHC and myogenin. Additionally, pretreatment with PD98059 and U0126 resulted in improved myotube formation and reduced BrdU staining in IL11-treated cells. Together, our results suggest that IL11 inhibits myogenic differentiation through delayed cell cycle exit in an ERK-dependent manner. To our knowledge, this study is the first to demonstrate an inhibitory role of IL11 in myogenic differentiation and identifies the previously unrecognized role of IL11 as a possible mediator of CAC.

Serum Interleukin-17 and its Correlation with Anti-CCP antibodies, Vitamin D3, and Obesity in Rheumatoid Arthritis women Patients

Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Members of the IL-17 cytokine family have various biological functions, including enhancing defense against multiple pathogens while promoting inflammatory pathology during autoimmune disease. Additionally, it has been suggested that vitamin D may be connected to the etiology of RA. Therefore, this study aimed to assess serum IL-17 and vitamin D3 concentrations in RA women and determine how these levels relate to anti-CCP, obesity, and age.Methods: This work included eighty women aged between (22-60) years. Sixty were afflicted with RA and attended the department of rheumatology and medical rehabilitation centre for rheumatic diseases at Rzgary teaching hospital-Erbil, Iraq, compared to twenty healthy women. The concentrations of Anti-CCP antibodies as a diagnostic test, Vitamin D3 and IL-17, were assessed by ELISA. The Mann-Whitney U test and normality were applied for the statistical analysis of the results. Also, the relationship between the study parameters was examined using Pearson's correlation. The ideal cutoff value for IL-17 with the highest sensitivity and specificity was detected using a Receiver Operating Characteristic (ROC) Curve. Results: This study revealed that serum IL-17 levels were significantly higher in RA women than in the control group (p &lt; 0.001) and that serum VD3 levels were significantly lower in RA women than in healthy controls. Seropositive anti-CCP Ab was found in about 42% of RA patients. The pro-inflammatory IL-17 serum level was positively correlated with vitamin D, age, and obesity in RA women. The best IL-17 cutoff for predicting the presence of RA was 69.5 pg/ML, with a sensitivity of 96% and a specificity of 75%. Conclusion: In patients with RA, vitamin D deficiency was common and correlated with age. Consequently, a high level of suspicion is needed when assessing at-risk patients, particularly women who complain of vitamin D deficiency.

Serum Levels of Selected IL-1 Family Cytokines in Patients with Morphea.

Morphea/localized scleroderma (LoS) represents an inflammatory-sclerotic skin disease, the pathogenesis of which is not fully understood. Given the important role of IL-1 family cytokines in the development and therapy of inflammatory diseases, including systemic sclerosis, we analyzed the clinical significance of serum levels of selected IL-1 family cytokines (IL-1α, IL-1β, IL-18, IL-33, IL-37 and IL-38) in LoS patients (n = 30) using the standardized disease assessment tools and comparison to healthy controls (n = 28). We also compared the pre- and post-treatment concentrations, i.e., before and after systemic (glucocorticosteroids and/or methotrexate) and/or topical (topical glucocorticosteroids and/or calcineurin inhibitors). Our findings did not reveal significant differences in baseline IL-1α, IL-1β, IL-18, IL-33, IL-37 and IL-38 levels between LoS group and HCs; however, after treatment, there were marked changes in concentrations of IL-1α and IL-33 within LoS group as well as in comparison to HCs. We also found significant negative correlations between PGA-A and IL-1α concentration as well as between mLoSSI and IL-1α after treatment. Furthermore, we showed an inverse correlation of baseline IL-1β levels with mLoSSI scores of borderline significance. We believe that IL-1α and IL-33, as well as Il-1β, may be potential mediators and targets of interest in LoS.