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Interleukin-27 (IL-27), a member of the IL-6/IL-12 family, has diverse regulatory functions in various immune responses, and is recognised as a potent agonist and antagonist of CD4+T cells in different contexts. However, this dual role and underlying mechanisms have not been completely defined. In the present review, we summarise the dual role of IL-27 in CD4+T cells. In particular, we aimed to decipher its mechanism to better understand the context-dependent function of IL-27 in CD4+T cells. Furthermore, we propose a possible mechanism for the dual role of IL-27. This may be helpful for the development of appropriate IL-27 treatments in various clinical settings. Show less

Axial spondyloarthritis (AxSpA) is an inflammatory disorder that affects the joints, entheses, and bone tissues and is sometimes associated with psoriasis, anterior uveitis, and gut inflammation. Its pathogenesis is not wholly understood and treatment strategies require optimization. Data concerning AxSpA pathogenesis support a critical role of abnormal CD4 Emerging drug targets in animal and cellular models and with phase-II clinical trials have been evaluated. We also reflect on key issues for preclinical and clinical research going forward. Some of the most promising approaches include: (i) modulation of transforming growth factor-β family that could exert a specific role on bone formation; (ii) blockade of granulocyte-macrophage colony-stimulating factor that could reduce type 3 immune responses, and (iii) rebalancing of biased immune response by cytokines such as IL-2 or IL-27 that could favor anti-inflammatory response and sustained drug-free remission. Multiomics tools and artificial intelligence could contribute to identification of optimal targets and help stratify patients for the most appropriate treatment options. Show less

Sporadic Alzheimer's disease (SAD) is a slowly progressive neurodegenerative disorder. This study aimed to investigate neuroprotective potential of tadalafil (TAD) and bergapten (BG) in SAD-induced cognitive impairment in mice. SAD was induced by single injection of streptozotocin (STZ; 3 mg/kg, ICV). STZ resulted in AD-like pathologies including Aβ deposition, tau aggregation, impaired insulin and Wnt/β-catenin signaling, as well as autophagic dysfunction and neuroinflammation. Administration of TAD or BG at doses of 20 and 25 mg/kg, respectively, for 21 consecutive days attenuated STZ-induced hippocampal insult, preserved neuronal integrity, and improved cognitive function in the Morris water maze and object recognition tests paralleled by reduction in Aβ expression by 79 and 89% and tau hyperphosphorylation by 60 and 61%, respectively. TAD and BG also enhanced protein expression of pAkt, pGSK-3β, beclin-1 and methylated protein phosphatase 2A (PP2A) and gene expression of cyclin D1, while raised BDNF immunoreactivity. Furthermore, TAD and BG boosted hippocampal levels of cGMP, PKG, Wnt3a, and AMPK and reduced expression of β-catenin and mTOR by 74% and 51%, respectively. TAD and BG also halted neuroinflammation by reducing IL-23 and IL-27 levels, as well as protein expression of NF-κB by 62% & 61%, respectively. In conclusion, this study offers novel insights on the neuroprotective effects of TAD or BG in the management of SAD as evidenced by improved cognitive function and histological architecture. This could be attributed to modulation of the crosstalk among PI3K/Akt/GSK-3β, PP2A, mTOR/autophagy, cGMP/PKG, and Wnt/β-catenin signaling cascades and mitigation of neuroinflammation. Show less

Multiple sclerosis (MS) is one of the most debilitating neurological diseases of young adults. The presence of a single nucleotide polymorphism in the promoter regions of the interleukin 27 gene (IL27 T4730C, rs181206) may alter the transcription and the production of cytokine levels, leading to MS. We performed a case-control study including 82 individuals: 51 patients diagnosed with MS and 31 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism was used in order to determine the genotypes for the IL27 T4730С polymorphism and enzyme-linked immunosorbent assay to measure the serum IL27 level. Carriers of the T4730С polymorphism were found to have a 6-fold [95% confidence intervaI (CI)=1.83-19.63, p=0.002] increased risk for MS. Univariate logistic regression analysis showed an increased frequency of the TC4730 heterozygous genotype (39.2% vs. 9.7%) and also of the C4730 allele (27.45% vs. 8.06) in patients compared to controls, with a 6.02-fold increased risk (95% CI=1.61-22.46, p=0.006) and a 4.31-fold increased risk (95% CI=1.57-11.87, p=0.002) of developing MS. IL27 levels were significantly lower in patients compared to controls (12.35 versus 14.34 pg/ml, p=0.039), without significant differences between genotypes. Multivariate logistic analysis showed that IL27 T4730C polymorphism (odds ratio=6.272, 95% CI=1.84-21.40, p=0.003) and smoking (odds ratio=4.214, 95% CI=1.39-12.74, p=0.011) represented independent risk factors for MS. Our study provides a possible link between IL27 level and IL27 T4730C gene polymorphism and the risk for developing MS in a Romanian population. Show less

The present study aimed to determine the diagnostic value of the serum levels and mutational status of IL-8, IL-27 and VEGF, and the expression levels of human ether-a-go-go-related gene (hERG) in patients with colorectal cancer (CRC). The serum concentrations were determined using the ELISA technique and genotype variations of IL-8, IL-27 and VEGF were examined using Sanger sequencing, and the expression levels of hERG, which encodes a potassium channel, were determined by quantitative PCR, in blood and tissue samples obtained from 80 patients with CRC and 80 healthy individuals. The results of the present study revealed that the percentage of granulocytes and serum concentrations of carcinoembryonic antigen, IL-8 and IL-27 were significantly increased, whereas the percentage of lymphocytes was decreased in patients with CRC. In total, 31 mutations in three genes (eight mutations in VEGF, 13 mutations in IL-27 and 10 mutations in IL-8) were identified in patients with CRC. The relative mRNA expression levels of hERG were also significantly upregulated in tissue and blood samples of patients with CRC compared with those of healthy individuals. In conclusion, the results of the present study indicated that the increased concentrations and genetic variations of IL-8, IL-27 and VEGF may serve important roles in the development and angiogenic processes of CRC. These changes were concomitant with the upregulation of the expression levels of the potassium channel hERG. Show less

Many RRMS patients who had been treated for over 20 years with GA 20 mg/ml daily (GA20) switched to 40 mg/ml three times-a-week (GA40) to reduce injection-related adverse events. Although GA40 is as effective as GA20 in reducing annualized relapse rate and MRI activity, it remains unknown how switching to GA40 from GA20 affects the development of pathogenic and regulatory immune cells. To investigate the difference in immunological parameters in response to GA20 and GA40 treatments. We analyzed five pro-inflammatory cytokines (IL-1β, IL-23, IL-12, IL-18, TNF-α), and three anti-inflammatory/regulatory cytokines (IL-10, IL-13, and IL-27) in serum. In addition, we analyzed six cytokines (IFN-γ, IL-17A, GM-CSF, IL-10, IL-6, and IL-27) in cultured PBMC supernatants. The development of Th1, Th17, Foxp3 Tregs, M1-like, and M2-like macrophages were examined by flow cytometry. Samples were analyzed before and 12 months post switching to GA40 or GA20. Pro- and anti-inflammatory cytokines were comparable between the GA40 and GA20 groups. Development of Th1, Th17, M1-like macrophages, M2-like macrophages, and Foxp3 Tregs was also comparable between the two groups. The immunological parameters measured in RRMS patients treated with GA40 three times weekly are largely comparable to those given daily GA20 treatment. Show less

Inflammation contributes to the pathogenesis of heart failure, but there is limited understanding of inflammation's potential benefits. Inflammatory cells secrete MYDGF (myeloid-derived growth factor) to promote tissue repair after acute myocardial infarction. We hypothesized that MYDGF has a role in cardiac adaptation to persistent pressure overload. We defined the cellular sources and function of MYDGF in wild-type (WT), MYDGF protein abundance increased in the left ventricular myocardium and in blood plasma of pressure-overloaded mice. Patients with severe aortic stenosis also had elevated MYDGF plasma concentrations, which declined after transcatheter aortic valve implantation. Monocytes and macrophages emerged as the main MYDGF sources in the pressure-overloaded murine heart. While These findings establish a MYDGF-based adaptive crosstalk between inflammatory cells and cardiomyocytes that protects against pressure overload-induced heart failure. Show less

Thoracic aortic aneurysms (TAA) are a progressive disease characterized by inflammation, smooth muscle cell activation and matrix degradation. We hypothesized that mesenchymal stem cells (MSCs) can immunomodulate vascular inflammation and remodeling via altered microRNA (miRNAs) expression profile to attenuate TAA formation. C57BL/6 mice underwent topical elastase application to form descending TAAs. Mice were also treated with MSCs on days 1 and 5 and aortas were analyzed on day 14 for aortic diameter. Cytokine array was performed in aortic tissue and total RNA was tagged and hybridized for miRNAs microarray analysis. Immunohistochemistry was performed for elastin degradation and leukocyte infiltration. Treatment with MSCs significantly attenuated aortic diameter and TAA formation compared to untreated mice. MSC administration also attenuated T-cell, neutrophil and macrophage infiltration and prevented elastic degradation to mitigate vascular remodeling. MSC treatment also attenuated aortic inflammation by decreasing proinflammatory cytokines (CXCL13, IL-27, CXCL12 and RANTES) and upregulating anti-inflammatory interleukin-10 expression in aortic tissue of elastase-treated mice. TAA formation demonstrated activation of specific miRNAs that are associated with aortic inflammation and vascular remodeling. Our results also demonstrated that MSCs modulate a different set of miRNAs that are associated with decrease leukocyte infiltration and vascular inflammation to attenuate the aortic diameter and TAA formation. These results indicate that MSCs immunomodulate specific miRNAs that are associated with modulating hallmarks of aortic inflammation and vascular remodeling of aortic aneurysms. Targeted therapies designed using MSCs and miRNAs have the potential to regulate the growth and development of TAAs. Show less

The placenta controls the growth of the fetus and ensures its immune protection. Key to these functions, the syncytiotrophoblast (SYN) is a syncytium formed by fusion of underlying mononuclear trophoblasts. The SYN covers the placental surface and is bathed in maternal blood to mediate nutritional and waste exchanges between the mother and fetus. The bacterial pathogen Show less

Neutrophilic asthmatics (NA) have less response to inhaled corticosteroids. We aimed to find out the predictor of treatment response in NA. Asthmatics (n = 115) and healthy controls (n = 28) underwent clinical assessment during 6-month follow-up with standardized therapy. Asthmatics were categorized by sputum differential cell count. The mRNA expressions were measured by RT-qPCR for sputum cytokines (IFN-γ, IL-1β, IL-27, FOXP3, IL-17A, and IL-5). The protein of IL-1β in sputum supernatant was detected by ELISA. Reticular basement membranes (RBM) were measured in the biopsy samples. The role and signaling pathways of IL-1β mediating the epithelial-mesenchymal transition (EMT) process were explored through A549 cells. NA had increased baseline sputum cell IL-1β expression compared to eosinophilic asthmatics (EA). After follow-up, NA had less improvement in FEV IL-1β level in baseline sputum predicts the poor lung function improvement in NA. The potential mechanism may be related to IL-1β augmenting TGF-β1-induced steroid-resistant EMT through MAPK signaling pathways. This study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (IRB ID: 20150406). Show less

IL-6 family cytokines display broad effects in haematopoietic and non-haematopoietic cells that regulate immune homeostasis, host defence, haematopoiesis, development, reproduction and wound healing. Dysregulation of these activities places this cytokine family as important mediators of autoimmunity, chronic inflammation and cancer. In this regard, ectopic lymphoid structures (ELS) are a pathological hallmark of many tissues affected by chronic disease. These inducible lymphoid aggregates form compartmentalised T cell and B cell zones, germinal centres, follicular dendritic cell networks and high endothelial venules, which are defining qualities of peripheral lymphoid organs. Accordingly, ELS can support local antigen-specific responses to self-antigens, alloantigens, pathogens and tumours. ELS often correlate with severe disease progression in autoimmune conditions, while tumour-associated ELS are associated with enhanced anti-tumour immunity and a favourable prognosis in cancer. Here, we discuss emerging roles for IL-6 family cytokines as regulators of ELS development, maintenance and activity and consider how modulation of these activities has the potential to aid the successful treatment of autoimmune conditions and cancers where ELS feature. Show less

Serum interleukin- (IL-) 27 level has been reported to increase in patients with several autoimmune diseases; however, its significance in patients with antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV) is unknown. In this study, we investigated the associations between serum IL-27, laboratory features, and activity of AAV and evaluate the predictive ability of serum IL-27 level for disease activity. This study included 77 AAV patients, and we collected clinical and laboratory data at blood sampling. Inflammation-related variables included white blood cell, neutrophil, lymphocyte and platelet counts, serum albumin, erythrocyte sedimentation rate, and C-reactive protein levels. Serum IL-27 and IL-18 levels were measured from stored sera using Human Magnetic Luminex® assay. High disease activity of AAV was defined as the highest tertile of Birmingham vasculitis activity score (BVAS) (≥11). The mean age of the enrolled patients was 59.9 years, and 38 (49.4%) were diagnosed as microscopic polyangiitis. In the multivariable analysis, serum albumin ( Show less

The IL-6 family of cytokines comprises a large group of cytokines that all act via the formation of a signaling complex that includes the glycoprotein 130 (gp130) receptor. Despite this, many of these cytokines have unique roles that regulate the activity of bone forming osteoblasts, bone resorbing osteoclasts, bone-resident osteocytes, and cartilage cells (chondrocytes). These include specific functions in craniofacial development, longitudinal bone growth, and the maintenance of trabecular and cortical bone structure, and have been implicated in musculoskeletal pathologies such as craniosynostosis, osteoporosis, rheumatoid arthritis, osteoarthritis, and heterotopic ossifications. This review will work systematically through each member of this family and provide an overview and an update on the expression patterns and functions of each of these cytokines in the skeleton, as well as their negative feedback pathways, particularly suppressor of cytokine signaling 3 (SOCS3). The specific cytokines described are interleukin 6 (IL-6), interleukin 11 (IL-11), oncostatin M (OSM), leukemia inhibitory factor (LIF), cardiotrophin 1 (CT-1), ciliary neurotrophic factor (CNTF), cardiotrophin-like cytokine factor 1 (CLCF1), neuropoietin, humanin and interleukin 27 (IL-27). Show less

Chikungunya virus (CHIKV) is known to have a wide range of tropism in human cell types throughout infection, including keratinocytes, fibroblasts, endothelial cells, monocytes, and macrophages. We reported that human monocytes-derived macrophages (MDMs) are permissive to CHIKV infection in vitro. We found that the peak of CHIKV replication was at 24 hpi; however, at 48 hpi, a significant reduction in viral titer was observed that correlated with high expression levels of genes encoding antiviral proteins (AVPs) in an IFN-independent manner. To explore the molecular mechanisms involved in the induction of antiviral response in CHIKV-infected MDMs, we performed transcriptomic analysis by RNA-sequencing. Differential expression of genes at 24 hpi showed that CHIKV infection abrogated the expression of all types of IFNs in MDMs. However, we observed that CHIKV-infected MDMs activated the JAK-STAT signaling and induced a robust antiviral response associated with control of CHIKV replication. We identified that the IL27 pathway is activated in CHIKV-infected MDMs and that kinetics of IL27p28 mRNA expression and IL27 protein production correlated with the expression of AVPs in CHIKV-infected MDMs. Furthermore, we showed that stimulation of THP-1-derived macrophages with recombinant-human IL27 induced the activation of the JAK-STAT signaling and induced a robust pro-inflammatory and antiviral response, comparable to CHIKV-infected MDMs. Furthermore, pre-treatment of MDMs with recombinant-human IL27 inhibits CHIKV replication in a dose-dependently manner (IC50 = 1.83 ng/mL). Altogether, results show that IL27 is highly expressed in CHIKV-infected MDMs, leading to activation of JAK-STAT signaling and stimulation of pro-inflammatory and antiviral response to control CHIKV replication in an IFN-independent manner. Show less

Cytokine polymorphisms have been associated with systemic lupus erythematosus (SLE) pathogenicity. Interleukin 27 (IL-27) is an important one of pro-/anti-inflammatory cytokine. It has been reported in various Th1/Th17-mediated inflammatory disorders, and even in Th2-complexed diseases, such as SLE. In our preliminary study, the aim was to investigate the potential roles of single nucleotide polymorphism (SNP) -964A/G (rs153109) and + 2905 T/G (rs17855750) in an IL-27p28 gene on susceptibility to SLE. The 112 Egyptian SLE patients against 101 healthy persons were enrolled in this work. The polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) is used for genotyping IL-27 SNPs. No significant variations were found between patients and control in the genotype and allele frequencies of IL-27p28 (-964A/G). SLE patients have a significant increase in the frequency of IL-27p28 (+ 2905 T/G) TG genotype (P < 0.01) and G allele (P < 0.01) compared to controls. Complete disappearance of GG genotype was demonstrated in both groups. G allele might have considered a disease risk factor with odd ration (OR) = 9.184. From four possible haplotypes, the frequency of AT haplotype elevated in both examined groups. This was the first study on the Egyptian population for studying the relation between IL-27 SNPs and SLE. Our preliminary study indicated that both TG genotype and G allele of IL-27p28 (+ 2905 T/G) could consider risk factors for SLE. Key Points • This article provides an information about the relation between systemic lupus erythematosus and interleukin-27 cytokine by detection single nucleotide polymorphism. Show less

Orientia tsutsugamushi is an obligately intracellular bacterium and the etiological agent of scrub typhus. The lung is a major target organ of infection, displaying type 1-skewed proinflammatory responses. Lung injury and acute respiratory distress syndrome are common complications of severe scrub typhus; yet, their underlying mechanisms remain unclear. In this study, we investigated whether the C-type lectin receptor (CLR) Mincle contributes to immune recognition and dysregulation. Following lethal infection in mice, we performed pulmonary differential expression analysis with NanoString. Of 671 genes examined, we found 312 significantly expressed genes at the terminal phase of disease. Mincle (Clec4e) was among the top 5 greatest up-regulated genes, accompanied with its signaling partners, type 1-skewing chemokines (Cxcr3, Ccr5, and their ligands), as well as Il27. To validate the role of Mincle in scrub typhus, we exposed murine bone marrow-derived macrophages (MΦ) to live or inactivated O. tsutsugamushi and analyzed a panel of CLRs and proinflammatory markers via qRT-PCR. We found that while heat-killed bacteria stimulated transitory Mincle expression, live bacteria generated a robust response in MΦ, which was validated by indirect immunofluorescence and western blot. Notably, infection had limited impact on other tested CLRs or TLRs. Sustained proinflammatory gene expression in MΦ (Cxcl9, Ccl2, Ccl5, Nos2, Il27) was induced by live, but not inactivated, bacteria; infected Mincle-/- MΦ significantly reduced proinflammatory responses compared with WT cells. Together, this study provides the first evidence for a selective expression of Mincle in sensing O. tsutsugamushi and suggests a potential role of Mincle- and IL-27-related pathways in host responses to severe infection. Additionally, it provides novel insight into innate immune recognition of this poorly studied bacterium. Show less

Immune thrombocytopenia (ITP) is an autoimmune-mediated disease characterized by decreased platelet counts. Cytokines play important roles in modulating the immune response and are involved in the pathogenesis of many autoimmune diseases. This study aimed at exploring the serum levels of a core set of cytokines that exert immune-regulatory functions in newly diagnosed ITP patients (both before and after treatment) and splenectomized ITP patients. Using the Bio-Plex suspension array system and ELISA, the serum levels of IL-10, IL-21, IL-27, IL-33, IL-35, IL-37, and TGF-β Show less

Glucocorticoids are a highly effective first-line treatment option for many inflammatory diseases, including asthma. Some patients develop a steroid-resistant condition, yet, the cellular and molecular mechanisms underlying steroid resistance remain largely unknown. In this study, we used a murine model of steroid-resistant airway inflammation and report that combining systemic dexamethasone and intranasal IL-27 is able to reverse the inflammation. Foxp3 Show less

Human uveitis is an autoimmune disease of the central nervous system that is characterized by ocular inflammation with the involvement of uveitogenic Th1 and Th17 responses. In experimental autoimmune uveitis (EAU), the animal model for human uveitis, both responses are proven to be critical in disease development. Therefore, targeting both Th1 and Th17 cells has therapeutic implication for disease resolution. IL-27 is a multifunctional cytokine that can either promote or inhibit T cell responses and is implicated in both autoimmune and infectious diseases. The aim of this study is to characterize the role of IL-27/IL-27R signaling in regulating uveitogenic Th1/Th17 responses in EAU. By immunizing IL-27Rα Show less

The strong genetic association between autoimmune regulator (AIRE) and autoimmune diseases indicates its critical role in immune tolerance. AIRE deficiency is thought to promote the development of follicular helper T (T Show less

Interleukin-27 (IL-27) is a cytokine that suppresses human immunodeficiency virus (HIV)-1 infection in macrophages and is considered as an immunotherapeutic reagent for infectious diseases. It is reported that IL-27 suppresses autophagy in Mycobacterium tuberculosis-infected macrophages; however, a role for IL-27 on autophagy induction has been less studied. In this study, we investigated the impact of IL-27 in both autophagy induction and HIV-1 infection in macrophages. Primary human monocytes were differentiated into macrophages using human AB serum (huAB) alone, macrophage-colony stimulating factor (M-CSF) alone, or a combination of IL-27 with huAB or M-CSF. Electron microscopy and immunofluorescence staining demonstrated that a 20-fold increase in autophagosome formation was only detected in IL-27 + huAB-induced macrophages. Western blot analysis indicated that the autophagosome induction was not linked to either dephosphorylation of the mammalian target of rapamycin (mTOR) or lipidation of microtubule-associated protein 1A/1B-light chain 3 (LC3), an autophagosomal marker, implying that IL-27 can induce autophagy through a novel non-canonical pathway. Here we show for the first time that IL-27 induces autophagy during monocyte-to-macrophage differentiation in a subtype-dependent manner. Show less

Preterm birth (PTB) is an immune-inflammatory disease that needs to be resolved. This study aimed to identify the role of interleukin-27 (IL-27), an immunomodulatory factor, in PTB and its associated mechanisms. Here, we analyzed the high-throughput of samples data from the maternal-fetal interface to the peripheral circulation obtained from public databases and reported that the elevated IL-27 was involved with the onset of PTB. Further bioinformatics analyses (e.g. GeneMANIA and GSEA) revealed that IL-27 overexpression in the peripheral circulation as well as maternal-fetal interface is related to the activation of the immune-inflammatory process represented by IFN-γ signaling, etc. In addition, IL-27 and immune infiltration correlation analysis demonstrated that IL-27 mediates this immune-inflammatory imbalance, plausibly mainly through monocyte-macrophage and neutrophils. This finding was further validated by analyzing additional datasets. Overall, this is the first study to elaborate on the role of IL-27-mediated immuno-inflammation in PTB from the perspective of bioinformatics, which may provide a novel strategy for the prevention and treatment of PTB. Show less

Cytokines control immune related events and are critically involved in a plethora of patho-physiological processes including autoimmunity and cancer development. In rare cases, single nucleotide polymorphisms (SNPs) or single nucleotide variations (SNVs) in cytokine receptors eventually cause detrimental ligand-independent, constitutive activation of signal transduction. Most SNPs have, however, no or only marginal influences on gene expression, protein stability, localization and function and thereby only slightly affecting pathogenesis probability. The SNP database (dbSNP) is an archive for a broad collection of polymorphisms in which SNPs are categorized and marked with a locus accession number "reference SNP" (rs). Here, we engineered an algorithm to directly align dbSNP information to DNA and protein sequence information to clearly illustrate a genetic SNP landscape exemplified for all tall cytokine receptors of the IL-6/IL-12 family, including IL-23R, IL-12Rβ1, IL-12Rβ2, gp130, LIFR, OSMR and WSX-1. This information was complemented by a comprehensive literature summary and structural insights of relevant disease-causing SNPs in cytokine/cytokine receptor interfaces. In summary, we present a general strategy with potential to apply to other cytokine receptor networks. Show less

Some cytokines can reengineer anti-tumor immunity to modify the tumor micro-environment. Interleukin-27 (IL-27) can partially reduce tumor growth in several animal models, including prostate cancer. We hypothesized that addition of IL-18, which can induce the proliferation of several immune effector cells through inducing IFNγ could synergize with IL-27 to enhance tumor growth control. We describe our findings on the effects of IL-27 gene delivery on prostate cancer cells and how sequential therapy with IL-18 enhanced the efficacy of IL-27. The combination of IL-27 followed by IL-18 (27→18) successfully reduced cancer cell viability, with significant effects in cell culture and in an immunocompetent mouse model. We also examined a novel chimeric cytokine, comprising an IL-27 targeted at the C-terminus with a short peptide, LSLITRL (27pepL). This novel cytokine targets a receptor upregulated in tumor cells (IL-6Rα) via the pepL ligand. Interestingly, when we compared the 27→18 combination with the single 27pepL therapy, we observed a similar efficacy for both. This efficacy was further enhanced when 27pepL was sequenced with IL-18 (27pepL→18). The observed reduction in tumor growth and significantly enriched canonical pathways and upstream regulators, as well as specific immune effector signatures (as determined by bioinformatics analyses in the tumor microenvironment) supported the therapeutic design, whereby IL-27 or 27pepL can be more effective when delivered with IL-18. This cytokine sequencing approach allows flexible incorporation of both gene delivery and recombinant cytokines as tools to augment IL-27's bioactivity and reengineer efficacy against prostate tumors and may prove applicable in other therapeutic settings. Show less

Neonates are at an increased risk of an infectious disease. This is consistent with an increased abundance of myeloid-derived suppressor cells (MDSCs) compared with older children and adults. Using a murine model of neonatal bacterial sepsis, we demonstrate that MDSCs modulate their activity during an infection to enhance immune suppressive functions. A gene expression analysis shows that MDSCs increased NOS2, Arg-1 and IL-27p28 expression in vitro and in vivo in response to Show less

Vascular endothelial cells activation and dysfunction mediate inflammation and abnormal coagulation in COVID-19 patients. Mineralocorticoid receptor (MR) signaling and its downstream target Galectin-3 (Gal-3) are known to mediate cardiovascular inflammation and might be involved in the pathogenesis of COVID-19 complications. Accordingly, we aimed to investigate the potential beneficial effects of MR antagonism and Gal-3 inhibition on the inflammatory response induced by SARS-CoV-2 Spike protein in human aortic endothelial cells (HAECs). HAECs were treated with recombinant SARS-COV2 Spike (S) protein. MR antagonists (namely spironolactone and eplerenone) or the Gal-3 inhibitor G3P-01 were supplemented before and after S protein challenge. HAECs supernatants were assessed by ELISA or Western blotting. HAECs treated with recombinant S protein resulted in enhanced secretion of inflammatory molecules (interleukin-6, monocyte chemoattractant protein-1, interleukin-18, interleukin-27, and interferon-γ) as well as in the thrombosis marker plasminogen activator inhibitor (PAI)-1. This was prevented and reversed by both MR antagonists and G3P-01. These findings indicate that MR/Gal-3 pathway blockade could be a promising option to reduce endothelial inflammation in SARS-CoV-2 infection. Show less

Autosomal recessive (AR) STAT1 deficiency is a severe inborn error of immunity disrupting cellular responses to type I, II, and III IFNs, and IL-27, and conferring a predisposition to both viral and mycobacterial infections. We report the genetic, immunological, and clinical features of an international cohort of 32 patients from 20 kindreds: 24 patients with complete deficiency, and 8 patients with partial deficiency. Twenty-four patients suffered from mycobacterial disease (bacillus Calmette-Guérin = 13, environmental mycobacteria = 10, or both in 1 patient). Fifty-four severe viral episodes occurred in sixteen patients, mainly caused by Show less

In neoplastic patients, an effective immune response ideally should be achieved by the coordinated action of different immune cells with tumor-suppressive functions. These include the more cytolytic members of the Innate Lymphoid Cells (ILCs) family represented by the Natural Killer (NK) cells, whose activities in cancer patients, however, can be hampered by several inhibitory signals. These are generated by membrane-bound and soluble molecules that, interacting with specific inhibitory receptors, create inhibitory axes impacting the NK cell differentiation and effector functions. These breaks, which now represent major immunotherapeutic targets, may be sensitive to interferon (IFN)-γ, whose source, in vivo, is represented by different cell types including the NK and ILC1. Since also ILCs can express receptors of the inhibitory axes like PD-1 and TIGIT, their therapeutic blockade might further amplify the IFN-γ release that, as an unwanted side effect, would promote the onset of NK cell-resistant tumor variants (NKRTV) expressing ligands involved in inhibitory axes. These variants might also arise from the activity of other cytokines such as IL-27, which can increase the expression of HLA class I and PD-Ls in different cell types, including tumor cells. Besides the amplification of membrane-bound inhibitory axes, tumors can reduce the number of infiltrating cytolytic ILCs, promote the recruitment of poorly cytolytic NK cell subsets, and manipulate to their advantage the infiltrating immune cells, which acquire tumor-promoting activities. This occurs thanks to the production of soluble factors including TGF-β1 and IL-18 that, alone or in combination, modify the activating and chemokine receptor repertoire of NK cells, and induce the ILCs differentiation towards cells ineffective in fighting cancer or, even worse, with tumor-promoting functions. The present review aims to present and discuss major inhibitory axes impacting on ILCs functions, migration, and differentiation with a major focus on tumor context. Show less