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We evaluated mRNA and miRNA in COVID-19 patients and elucidated the pathogenesis of COVID-19, including protein profiles, following mRNA and miRNA integration analysis. mRNA and miRNA sequencing was done on admission with whole blood of 5 and 16 healthy controls (HCs) and 10 and 31 critically ill COVID-19 patients (derivation and validation cohorts, respectively). Interferon (IFN)-α2, IFN-β, IFN-γ, interleukin-27, and IFN-λ1 were measured in COVID-19 patients on admission (day 1, 181 critical/22 non-critical patients) and days 6-8 (168 critical patients) and in 19 HCs. In the derivation cohort, 3,488 mRNA and 31 miRNA expressions were identified among differentially expressed RNA expressions in the patients versus those in HCs, and 2,945 mRNA and 32 miRNA expressions in the validation cohort. Canonical pathway analysis showed the IFN signaling pathway to be most activated. The IFN-β plasma level was elevated in line with increased severity compared with HCs, as were IFN-β downstream proteins, such as interleukin-27. IFN-λ1 was higher in non-critically ill patients versus HCs but lower in critical than non-critical patients. Integration of mRNA and miRNA analysis showed activated IFN signaling. Plasma IFN protein profile revealed that IFN-β (type I) and IFN-λ1 (type III) played important roles in COVID-19 disease progression. Show less

African swine fever (ASF) is a lethal hemorrhagic disease affecting domestic pigs resulting in up to 100% mortality rates caused by the ASF virus (ASFV). The locally-adapted pigs in South-western Kenya have been reported to be resilient to disease and harsh climatic conditions and tolerate ASF; however, the mechanisms by which this tolerance is sustained remain largely unknown. We evaluated the gene expression patterns in spleen tissues of these locally-adapted pigs in response to varying infective doses of ASFV to elucidate the virus-host interaction dynamics. Locally adapted pigs (n = 14) were experimentally infected with a high dose (1x10 A total of 4954 differentially expressed genes (DEGs) were detected after ASFV Ken12/1 infection, including 3055, 1771, and 128 DEGs in the high, medium, and low doses, respectively. Gene ontology and KEGG pathway analysis showed that the DEGs were enriched for genes involved in the innate immune response, inflammatory response, autophagy, and apoptosis in lethal dose groups. The surviving low dose group suppressed genes in pathways of physiopathological importance. We found a strong association between severe ASF pathogenesis in the high and medium dose groups with upregulation of proinflammatory cytokines and immunomodulation of cytokine expression possibly induced by overproduction of prostaglandin E synthase (4-fold; p < 0.05) or through downregulation of expression of M1-activating receptors, signal transductors, and transcription factors. The host-pathogen interaction resulted in induction of expression of immune-suppressive cytokines (IL-27), inactivation of autophagy and apoptosis through up-regulation of NUPR1 [5.7-fold (high dose) and 5.1-fold (medium dose) [p < 0.05] and IL7R expression. We detected repression of genes involved in MHC class II antigen processing and presentation, such as cathepsins, SLA-DQB1, SLA-DOB, SLA-DMB, SLA-DRA, and SLA-DQA in the medium and high dose groups. Additionally, the host-pathogen interaction activated the CD8 We provide the first in vivo gene expression profile data from locally-adapted pigs from south-western Kenya following experimental infection with a highly virulent ASFV genotype IX isolate at varying doses that mimic acute and mild disease. Our study showed that the locally-adapted pigs induced the expression of genes associated with tolerance to infection and repression of genes involved in inflammation at varying levels depending upon the ASFV dose administered. Show less

Rheumatoid arthritis (RA) is a highly prevalent autoimmune condition associated with pronounced synovial inflammation. The majority of RA patients required long-term treatment to control disease progression, thus imposing a significant financial burden on affected individuals. The development of RA is critically influenced by fibroblast-like synoviocytes (FLSs) within the synovial lining. IL-27 is an IL-6/IL-12 family cytokine that has recently been shown to play varied pro-inflammatory or protective roles in particular autoimmune diseases. However, the effects of IL-27 on FLSs in the context of RA have yet to be clarified and warrant further research. This study was developed to evaluate the impact of IL-27 treatment on apoptotic and autophagic activity in RA-associated FLSs, with a particular focus on the role of the STAT3 pathway in this regulatory context. Through these experiments, we found that IL-27 was able to suppress FLS proliferation and autophagic activity, with a high dose of this cytokine (100 ng/mL) markedly suppressing autophagy while simultaneously inducing some level of cellular apoptosis. The STAT3 inhibitor STA21 was found to reverse the IL-27-mediated suppression of autophagic activity in these RA-associated FLSs. Imbalanced cellular proliferation and apoptosis is of critical importance in the context of RA progression, and we found that IL-27 was able to regulate such imbalance and to enhance the apoptotic activity of RA FLSs by inhibiting rapamycin-activated autophagy. Together, these results indicate that IL-27 can regulate autophagic activity within RA-associated FLSs via the STAT3 signaling pathway, leading to inhibition of cellular proliferation. Show less

Pleural effusion is a common clinical condition caused by several respiratory diseases, including tuberculosis and malignancy. However, rapid and accurate diagnoses of tuberculous pleural effusion (TPE) and malignant pleural effusion (MPE) remain challenging. Although monocytes have been confirmed as an important immune cell in tuberculosis and malignancy, little is known about the role of monocytes subpopulations in the diagnosis of pleural effusion. Pleural effusion samples and peripheral blood samples were collected from 40 TPE patients, 40 MPE patients, and 24 transudate pleural effusion patients, respectively. Chemokines (CCL2, CCL7, and CX3CL1) and cytokines (IL-1β, IL-17, IL-27, and IFN-γ) were measured by ELISA. The monocytes phenotypes were analyzed by flow cytometry. The chemokines receptors (CCR2 and CX3CR1) and cytokines above in different monocytes subsets were analyzed by real-time PCR. Receiver operating characteristic curve analysis was performed for displaying differentiating power of intermediate and nonclassical subsets between tuberculous and malignant pleural effusions. CCL7 and CX3CL1 levels in TPE were significantly elevated in TPE compared with MPE and transudate pleural effusion. Cytokines, such as IL-1β, IL-17, IL-27, and IFN-γ, in TPE were much higher than in other pleural effusions. Moreover, CD14 CD14 and CD16 markers on monocytes could be potentially used as novel diagnostic markers for diagnosing TPE and MPE. Show less

We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425). In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy. A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1-2 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55-40.5). Three patients developed a partial response (PR) (ORR = 25%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4 Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy. ClinicalTrials.gov, NCT02856425 . Registered August 4, 2016 - Prospectively registered. Show less

To investigate the correlation between interleukin-27 and CXCL10 and other cytokines in pulmonary tuberculosis and to further explore the related miRNAs through bioinformatics. Collect the lesion tissue and peripheral blood of pulmonary tuberculosis patients and the peripheral blood of healthy controls. Immunohistochemical staining and qRT-PCR were used to observe the expression of interleukin-27, CXCL9, CXCL10, and CXCL11. Then, predict the key miRNA, qRT-PCR was used to verify the expression of miRNA in the peripheral blood and evaluated the correlation between them. Both immunohistochemical staining and qRT-PCR indicated that the expressions of IL-27, CXCL9, CXCL10, and CXCL11 were significantly increased in tuberculosis patients, and IL-27 was significantly correlated with CXCL10 ( Our data shows that interleukin-27 and CXCL10 are significantly related in pulmonary tuberculosis, and has-let-7b-5p and has-miR-30a-3p are also related to interleukin-27 and CXCL10. It laid the foundation for subsequently exploiting the potential biomarkers in tuberculosis disease. Show less

Congestive heart failure is a complex multifactorial syndrome due to tissue hypoperfusion that is affected by some factors like inflammatory cytokines. In our study, we investigated the exact gene expression of three inflammatory cytokines in ischemic and idiopathic cardiomyopathy patients. From 49 studied recipients in the ischemic group, 23 (46.9%) were male and from 40 studied recipients in the idiopathic dilated cardiomyopathy group, 19 (47.5%) were male. For the quantitative analysis of interleukin (IL)-1, IL-27, and tumor necrosis factor (TNF)-α messenger RNAs expression level, the SYBR Green real-time polymerase chain reaction method was performed using SYBRPremix Ex TaqTM II (Tli RNaseH Plus; Takara) and designed primers specific for each gene in an iQ5 thermocycler (BioRad Laboratories) according to the manufacturer's instructions. Our results showed that the expression level of IL-1 and TNF-α were significantly higher in the ischemic patients compared to healthy controls ( Although we would introduce IL-1, IL-27, and TNF-α as effective inflammatory cytokines on myocardial functions in ischemic and idiopathic cardiomyopathy patients, there is not any difference between these two groups in gene expression of three main inflammatory cytokines. Show less

Staphylococcus aureus persistently colonises the anterior nares of a significant proportion of the healthy population, however the local immune response elicited during S. aureus nasal colonisation remains ill-defined. Local activation of IL-17/IL-22 producing T cells are critical for controlling bacterial clearance from the nasal cavity. However, recurrent and long-term colonisation is commonplace indicating efficient clearance does not invariably occur. Here we identify a central role for the regulatory cytokine IL-10 in facilitating bacterial persistence during S. aureus nasal colonisation in a murine model. IL-10 is produced rapidly within the nasal cavity following S. aureus colonisation, primarily by myeloid cells. Colonised IL-10-/- mice demonstrate enhanced IL-17+ and IL-22+ T cell responses and more rapidly clear bacteria from the nasal tissues as compared with wild-type mice. S. aureus also induces the regulatory cytokine IL-27 within the nasal tissue, which acts upstream of IL-10 promoting its production. IL-27 blockade reduces IL-10 production within the nasal cavity and improves bacterial clearance. TLR2 signalling was confirmed to be central to controlling the IL-10 response. Our findings conclude that during nasal colonisation S. aureus creates an immunosuppressive microenvironment through the local induction of IL-27 and IL-10, to dampen protective T cell responses and facilitate its persistence. Show less

Concepts surrounding the mechanisms of thrombocytopenia in ITP have shifted from the traditional view of autoantibody mediated platelet destruction to more complex mechanisms in which impaired platelet production, T-cell-mediated effects, and disturbed cytokine profiles play a role. Interleukin 27 (IL-27) plays pleiotropic roles in immunomodulation and autoimmune diseases.We aimed to determine the level of IL-27 in patients with ITP and its relationship to patient and disease characteristics as well as disease chronicity and response to treatment.Sixty childrens with primary immune thrombocytopenia were consequetively enrolled in this study as well as 20 age and sex matched healthy controls.ITP patients had significantly higher levels of IL-27 than controls (770.6 and 373.8 pg/ml, respectively). Patients with acute ITP had the highest levels of IL-27 among patient groups, while patients in remission had the lowest IL-27 levels (860.1and 622.9 pg/ml, respectively). Patients who received IVIG and combined steroids plus IVIG had significantly higher IL-27 levels than others. Patients who received Eltrombopag had significantly lower IL-27 levels than others.IL-27 seems to play a role in pathogenesis of childhood ITP. IL-27 can be used as a predictor for disease occurrence as well as responsiveness to treatment. Show less

Breast cancer is considered refractory to immunotherapy. Accordingly, there is an urgent need for the therapeutic use of new immunostimulatory agents which would enhance antitumor immune response against breast cancer cells. "Derived Multiple Allogeneic Protein Paracrine Signaling (d-MAPPS)" is a biological product whose activity is based on chemokines and cytokines that modulate homing and phenotype of immune cells. d-MAPPS contains high concentration of dendritic cell (DC) and T cell-attracting chemokine CXCL16 and potent T cell-activating cytokine IL-27 which enhance DC:T cell cross-talk in inflamed tissues. Herewith, we used 4T1 murine model of breast cancer to analyze d-MAPPS-dependent enhancement of T cell-driven antitumor immunity. 4T1+d-MAPPS-treated mice showed delayed mammary tumor appearance compared to 4T1+saline-treated animals. d-MAPPS significantly reduced tumor weight and volume and improved survival of 4T1-treated mice. Significantly increased concentration of CXCL16, IL-27, IFN- Show less

Nitrite is a ubiquitous toxic compound in aquatic ecosystems and has negative effects on aquatic organisms. The intestine and the trillions of microbes that inhabit it, play an integral role in maintaining digestive and immune functions. However, the effects of nitrite on intestinal health and microflora have been poorly investigated. Therefore, the present study evaluated the response of intestinal histology, immunity, digestive enzyme activities and microbiota to nitrite exposure in Bufo gargarizans tadpoles. The results showed that nitrite caused damage to the intestine and impaired digestive performance. Significant changes in the transcriptional profiles of genes involved in oxidative stress (sod, gpx and hsp), inflammation, and immunity (socs3, il-27, il-1β and il-17d) were observed in the NO Show less

Rheumatoid arthritis (RA) is a chronic autoimmune disease which is characterized primarily by synovial hyperplasia and accumulation of several types of immune infiltrates that promote progressive destruction of the articular structure. Glucocorticoids are often prescribed to treat RA because of their strong anti-inflammatory and immunosuppressive effects. However, their application must be limited to the short-term due to a risk of adverse events. In the present study, we examined the potential combination of low-dose prednisone with gene delivery of an agent of promising and complementary effectiveness in RA, interleukin (IL)-27. IL-27 has been shown to have anti-inflammatory potential, while also acting as an effective bone-normalization agent in prior reports. The present report examined a version of IL-27 targeted at the C-terminus with a short 'peptide L' (pepL, LSLITRL) that binds the interleukin 6 receptor α (IL-6Rα) upregulated during inflammation. By focusing on this targeted form, IL-27pepL or 27pL, we examined whether the anti-inflammatory potential of prednisone (at a relatively low dose and short duration) could be further enhanced in the presence of 27pL as a therapy adjuvant. Our results indicate that 27pL represents a novel tool for use as an adjuvant with current therapeutics, such as prednisone, against inflammatory conditions. Show less

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme 2 (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in the alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis is still elusive. Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 "gain-of-function" experiments were applied to infected human lung explants and adult stem cell derived human lung organoids to correlate ACE2 and related host factors with SARS-CoV-2 tropism, propagation, virulence and immune activation compared to SARS-CoV, influenza and Middle East respiratory syndrome coronavirus (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used to validate We provide evidence that alveolar ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation and virus-induced tissue damage in the human alveolus. Instead, Collectively, our findings indicate that severe lung injury in COVID-19 probably results from a macrophage-triggered immune activation rather than direct viral damage of the alveolar compartment. Show less

Although inflammatory mechanisms driving hepatocellular carcinoma (HCC) have been proposed, the regulators of anticancer immunity in HCC remain poorly understood. We found that IL27 receptor (IL27R) signaling promotes HCC development in vivo. High IL27EBI3 cytokine or IL27RA expression correlated with poor prognosis for patients with HCC. Loss of IL27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL27R sig-naling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL27R ablation enhanced their accumulation and activation, whereas depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL27R disruption. Pharmacologic neutralization of IL27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL27R signaling as an immunologic checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL27 pathway blockade in HCC. HCC, the most common form of liver cancer, is characterized by a poor survival rate and limited treatment options. The discovery of a novel IL27-dependent mechanism controlling anticancer cytotoxic immune response will pave the road for new treatment options for this devastating disease. This article is highlighted in the In This Issue feature, p. 1825. Show less

: The aim of this study was to assess the performance of kynurenine/tryptophan ratio for tuberculosis (TB) case-finding among antiretroviral therapy (ART)-naive people with HIV (PWH), and to investigate other factors associated with kynurenine/tryptophan ratio in this population. : A nested case--control study based on a cohort of 812 ambulatory PWH in the Oromia region, Ethiopia. : At enrolment, all participants submitted sputum samples for bacteriological TB investigations. Concentrations of kynurenine and tryptophan in plasma were quantified using liquid chromatography-mass spectrometry. Receiver operator characteristic curves were constructed to assess diagnostic performance (area under the curve; AUC) for kynurenine, tryptophan, and kynurenine/tryptophan ratio. Sensitivity, specificity, and predictive values were calculated. Kynurenine/tryptophan ratios were correlated to plasma levels of nine inflammation mediators, plasma HIV RNA levels, CD4 + cell count, BMI, and mid-upper arm circumference (MUAC). : We included 124 individuals with HIV-TB coinfection (HIV+/TB+) and 125 with HIV mono-infection (HIV+/TB-). Tryptophan levels were lower in HIV+/TB+ than in HIV+/TB- (median 19.5 vs. 29.8 μmol/l, P  < 0.01), while kynurenine levels were similar between these groups (median 2.95 vs. 2.94 μmol/l, P  = 0.62). Median kynurenine/tryptophan ratio was 0.15 in HIV+/TB+, significantly higher compared with HIV+/TB- (0.11; P  < 0.01), with AUC 0.70 for TB detection. Kynurenine/tryptophan ratio was positively correlated to plasma HIV RNA levels, IP-10, IL-18, and IL-27, and negatively correlated to CD4 + cell count, BMI, and MUAC (all P  < 0.01). : Among ART-naive PWH, kynurenine/tryptophan ratio has modest potential for TB discrimination, limiting its utility for TB case-finding in this population. Show less

To investigate the mechanism of serum interleukin-6 (IL-6) change in disease progression of interstitial nephritis. This is a retrospective study. From November 2017 to November 2019, 87 patients with interstitial nephritis treated in our hospital were enrolled and divided into an acute group (n=42) and a chronic group (n=45) based on pathological results of renal biopsies. Forty healthy individuals after physical examination during the same period were enrolled into the reference group. Serum IL-6 levels were determined using the enzyme-linked immunosorbent assay (ELISA). Among the three groups, patients in the acute group showed the highest IL-6 level (P<0.001). The acute group obtained higher serum advanced oxidation protein products (AOPP) levels and glomerular filtration rate (GFR) than the other two groups (P<0.05). The acute group showed lower levels of CD34 Serum IL-6 shows a great potential as an important marker of disease progression in interstitial nephritis. Show less

Tick-borne encephalitis (TBE) usually has a biphasic course which begins with unspecific febrile illness, followed by central nervous system involvement. Because TBE is not yet suspected during the initial phase, knowledge of early TBE pathogenesis is incomplete. Herein we evaluated laboratory and immune findings in the initial and second (meningoencephalitic) phase of TBE in 88 well-defined adult patients. Comparison of nine laboratory blood parameters in both phases of TBE revealed that laboratory abnormalities, consisting of low leukocyte and platelet counts and increased liver enzymes levels, were predominately associated with the initial phase of TBE and resolved thereafter. Assessment of 29 immune mediators in serum during the initial phase, and in serum and cerebrospinal fluid (CSF) during the second phase of TBE revealed highly distinct clustering patterns among the three groups. In the initial phase of TBE, the primary finding in serum was a rather heterogeneous immune response involving innate (CXCL11), B cell (CXCL13, BAFF), and T cell mediators (IL-27 and IL-4). During the second phase of TBE, growth factors associated with angiogenesis (GRO-α and VEGF-A) were the predominant characteristic in serum, whereas innate and Th1 mediators were the defining feature of immune responses in CSF. These findings imply that distinct immune processes play a role in the pathophysiology of different phases of TBE and in different compartments. Show less

Interleukin 17D (IL-17D), a pro-inflammatory cytokine, is a signature cytokine of T helper 17 (Th17) cells. However, studies characterizing the functions of IL-17D in teleost are scarce. Therefore, we aimed to characterize the properties of IL-17D in Amphiprion clarkii. We performed spatial and temporal expression, AcIL-17D-mediated antibacterial and inflammatory gene expression, NFκB pathway-related gene expression analyses, and bacterial colony counting and cell protection assays. We found that AcIL-17D contains a 630 bp coding sequence and encodes 210 amino acids. The spatial expression analysis of AcIL-17D in 12 tissues showed ubiquitous expression, with the highest expression in the brain, followed by blood and skin. Temporal expression analysis of AcIL-17D in blood showed upregulated expression at 6 and 24 h (polyinosinic: polycytidylic acid and lipopolysaccharide), 12 h (all stimulants), and 48 h (polyinosinic: polycytidylic acid and Vibrio harveyi). AcIL-17D expression in the blood gradually decreased at later hours in response to all the stimulants. After treatment of fathead minnow (FHM) cells with different recombinant AcIL-17D concentrations, the downstream gene expression analysis showed increased expression of antimicrobial genes in the FHM cells, namely [NK-Lysin (NKL), Hepcidin antimicrobial peptide-1 (HAMP-1), Defensin-β (DEFB1)] and some inflammatory genes such as IL-1β, TNF-α, IL-11, and STAT3. Further nuclear factor κB (NFκB) subunits (NFκB1, NFκB2, RelA, and Rel-B) showed upregulated gene expression at 12 and 24 h. The bacterial colony counting assay using FHM cells showed lower bacterial colony counts in rAcIL-17D-treated cells than in control. Furthermore, the Water-Soluble Tetrazolium Salt (WST -1) assay confirmed the ability of rAcIL-17D in the protection of FHM cells from bacterial infection and conducted the Hoechst 33342 staining upon treatment with rAcIL-17D and rMBP. Therefore, our findings provide important insights into the activation of IL-17D pathway genes in FHM cells, the protective role of AcIL-17D against bacterial infection, and host defense mechanisms in teleost. Show less

Emergence of new, pandemic-level viral threats has brought to the forefront the importance of viral immunology and continued improvement of antiviral therapies. Interleukin-27 (IL-27) is a pleiotropic cytokine that regulates both innate and adaptive immune responses. Accumulating evidence has revealed potent antiviral activities of IL-27 against numerous viruses, including HIV, influenza, HBV and more. IL-27 contributes to the immune response against viruses indirectly by increasing production of interferons (IFNs) which have various antiviral effects. Additionally, IL-27 can directly interfere with viral infection both by acting similarly to an IFN itself and by modulating the differentiation and function of various immune cells. This review discusses the IFN-dependent and IFN-independent antiviral mechanisms of IL-27 and highlights the potential of IL-27 as a therapeutic cytokine for viral infection. Show less

To explore the diagnosis value of inflammatory markers and cytokines in neonatal sepsis. In this retrospective analysis, 90 cases of neonatal sepsis admitted to our hospital from April 2019 to April 2021 were included in the observation group, and 70 healthy neonates who received routine physical examinations in our hospital during the same period were recruited as the control group. Comparison and analysis of inflammatory markers and cytokines levels between the two groups were performed on days 1, 3, and 7 after the onset. Flow cytometry was used to measure the white blood cells (WBCs) and percentage of neutrophils (N%), immunoturbidimetry was used to determine C-reactive protein (CRP), immunochromatographic analysis was used to determine procalcitonin (PCT) in plasma, and the enzyme-linked immunosorbent assay was used to determine interleukin-27 (IL-27), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor- Compared with healthy controls, neonatal sepsis resulted in significantly higher levels of WBC, N%, PCT, and CRP on days 1, 3, and 7 after onset. The levels of WBC, N%, and PCT were continuously decreased from day 1 to day 7, while the levels of CRP were increased on day 1 and day 3 but declined on day 7 ( Neonatal sepsis was associated with fluctuating levels of WBC, N%, PCT, CRP, IL-27, IL-6, IL-10, and TNF- Show less

Cytokines are a group of immunomodulatory proteins leading to a variety of immune reactions in the human; these cytokines play a significant role in the development of appropriate immune responses against T. gondii. This study aims to reveal the association of toxoplasmosis with serum levels of IL-3, IL-17A, and IL-27 in aborted women. The blood samples of patients and controls were collected from Al-Alawiya Maternity Teaching Hospital/Baghdad/Iraq from 2019 to 2020 for detecting anti-T. gondii antibodies (IgG and IgM) and the level of interleukins by ELISA. The results of TORCH by rapid test for recurrent abortion recorded 25.3% seropositive for anti-Toxoplasma antibodies, and 31.5% seropositive for one or more cases of TORCH test (Cytomegalovirus, Rubella, and Herpes). Whereas the results for anti-T. gondii IgG and IgM antibodies were shown elevated positivity percentages by ELISA test; these percentages were 56.2% in recurrent abortion women with significant differences (P < 0.05). The results suggested that the IL-3 serum concentration of pregnant women, recurrent abortion, and recurrent abortion with toxoplasmosis was declined versus healthy women with significant differences (p < 0.05). However, the results revealed that the concentration of IL-17A in recurrent abortion, and recurrent abortion with toxoplasmosis elevated versus healthy women and pregnant women with significant difference (p < 0.05). Whereas the results indicated that the IL-27 serum concentration elevated with significant differences in recurrent abortion with toxoplasmosis group compared to healthy women, pregnant women, and recurrent abortion. Interestingly, the serum levels for IL-27 increased comparing to the levels of IL-3 and IL-17A in all groups with significant differences (P < 0.05). In conclusion, it appeared in this study that the role of IL-3, IL-17A, and IL-27 in the maternal immune response during infections can lead to abortion. Show less

Sickle cell disease (SCD) is a well-studied monogenetic disease with an established chronic inflammatory component. The paradigm shift towards inflammation has made the pathophysiology of SCD even more complex. Studies have shown that an imbalance between the pro-inflammatory and anti-inflammatory cytokines in SCD exists; however, the reports are skewed toward the pro-inflammatory mediators. We enumerate recent in vitro and in vivo studies on anti-inflammatory cytokines in SCD patients, and discuss the biology of anti-inflammatory cytokines including the already reported IL-2, TGF-β, and IL-10 as well as the recently discovered IL-27, IL-35 and IL-37. This review will improve the understanding of the pathophysiology of SCD and aid in the search of new therapeutic options for patients with SCD. Show less

Interleukin 27 (IL-27) is a heterodimeric cytokine that functions to constrain T cell-mediated inflammation and plays an important role in immune homeostasis. Binding of IL-27 to cell surface receptors, IL-27Rα and gp130, results in activation of receptor-associated Janus Kinases and nuclear translocation of Signal Transducer and Activator of Transcription 1 (STAT1) and STAT3 transcription factors. Despite the emerging therapeutic importance of this cytokine axis in cancer and autoimmunity, a molecular blueprint of the IL-27 receptor signaling complex, and its relation to other gp130/IL-12 family cytokines, is currently unclear. We used cryogenic-electron microscopy to determine the quaternary structure of IL-27, composed of p28 and Epstein-Barr Virus-Induced 3 (Ebi3) subunits, bound to receptors, IL-27Rα and gp130. The resulting 3.47 Å resolution structure revealed a three-site assembly mechanism nucleated by the central p28 subunit of the cytokine. The overall topology and molecular details of this binding are reminiscent of IL-6 but distinct from related heterodimeric cytokines IL-12 and IL-23. These results indicate distinct receptor assembly mechanisms used by heterodimeric cytokines with important consequences for targeted agonism and antagonism of IL-27 signaling. Show less

The protocol used to induce cell death for generating vaccines from whole tumor cells is a critical consideration that impacts vaccine efficacy. Here we compared how different protocols used to induce cell death impacted protection provided by a prophylactic whole tumor cell vaccine in a mouse melanoma model. We found that melanoma cells exposed to γ-irradiation or lysis combined with UV-irradiation (LyUV) provided better protection against tumor challenge than lysis only or cells exposed to UV-irradiation. Furthermore, we found that the immunoregulatory cytokine, IL-27 enhanced protection against tumor growth in a dose-dependent manner when combined with either LyUV or γ-irradiated whole tumor cell vaccine preparations. Taken together, this data supports the use of LyUV as a potential protocol for developing whole tumor cell prophylactic cancer vaccines. We also showed that IL-27 can be used at low doses as a potent adjuvant in combination with LyUV or γ-irradiation treated cancer cells to improve the protection provided by a prophylactic cancer vaccine in a mouse melanoma model. Show less

To study the significance of interleukin-6 (IL-6) and interleukin-27 (IL-27) in the differential diagnosis of acute respiratory distress syndrome (ARDS) and neonatal respiratory distress syndrome (NRDS) in preterm infants. The preterm infants with the manifestation of respiratory distress who were treated in the Neonatal Diagnosis and Treatment Center, Children's Hospital of Chongqing Medical University, from March to November 2021, were enrolled in this prospective study. According to the diagnosis results, they were divided into two groups: ARDS group ( The ARDS group had significantly higher plasma levels of IL-6 and IL-27 than the NRDS group ( Plasma IL-6 and IL-27 can be used as biological indicators for early differential diagnosis of ARDS and NRDS in preterm infants. Show less

IL-27 is a member of the IL-12 family, exerting both anti- and pro-inflammatory activity in a cell-dependent and disease context-specific manner. Antigen-mediated cross-linking of IgE on mast cells triggers a signaling cascade that results in mast cell degranulation and proinflammatory cytokine production, which are key effectors in allergic reactions. Here, we show that the activation of mast cells is negatively regulated by IL-27 signaling. We found that mice lacking IL-27Rα (WSX-1) displayed increased sensitivity to IgE-mediated skin allergic response and chronic airway inflammation. The bone marrow-derived mast cells (BMMCs) of IL-27Rα-deficient mouse showed greater high-affinity receptor Fc epsilon RI (FcεRI)-mediated activation with significantly enhanced degranulation and cytokine production. Mechanistically, the dysregulated signaling in IL-27Rα Show less

Gestational diabetes (GDM) is characterized by low-grade systemic inflammation, which manifests as changes in the levels of cytokines in the blood. We aimed to investigate plasma immune mediators during gestational weeks 23-28 in 213 women at risk for GDM, and to find associations between GDM and its complications. We quantified the levels of adipokines: adiponectin, leptin, plasminogen activator inhibitor-1 and resistin; chemokines: C-C motif chemokine ligand 2 (CCL2), CCL4, C-X-C motif chemokine ligand 8 (CXCL8) and CXCL10; and cytokines: granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-1β, soluble (s)IL-1RI, IL-2, sIL-2Ra, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12(p70), IL-13, IL-15, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-27, transforming growth factor (TGF)-β1, TGF-β2, TGF-β3, tumor necrosis factor-α and soluble tumor necrosis factor receptor 2 using the Milliplex®MAP Magnetic Bead assay on Luminex®200™, and compared the results with clinical data from pregnancy and post-partum follow up. Lower levels of adiponectin and higher levels of CCL2 (Wilcoxon test, P = 3.4E-03 and P = 0.03, respectively) were found in women with GDM. IL-27 levels were associated with lower odds of GDM (adjusted logistic regression 0.90, P = 2.4E-03), and showed a risk association with glutamic acid decarboxylase autoantibody positivity (adjusted odds ratio 1.13, P = 2.8E-03). Similarly, higher IL-22 levels increased the odds of glutamic acid decarboxylase autoantibody positivity (adjusted odds ratio 4.23, P = 0.04). TGF-β1 was associated with post-partum fasting glucose levels, and CCL4 with post-partum C-peptide levels (linear regression, P = 0.04 and P = 0.01, respectively). Women who developed pregnancy complications had higher levels of CXCL10 and CCL4 (linear regression, P = 7.0E-04 and P = 0.01, respectively). Plasma adiponectin and CCL2 concentrations distinguish women with GDM. IL-27 and IL-22 levels might select women with an autoimmune reaction, whereas increased TGF-β1 and CCL4 are associated with post-partum glucose and insulin metabolism. Show less