IL-27 signalling promotes adipocyte thermogenesis and energy expenditure.

Thermogenesis in brown and beige adipose tissue has important roles in maintaining body temperature and countering the development of metabolic disorders such as obesity and type 2 diabetes1,2. Although much is known about commitment and activation of brown and beige adipose tissue, its multiple and abundant immunological factors have not been well characterized3-6. Here we define a critical role of IL-27-IL-27Rα signalling in improving thermogenesis, protecting against diet-induced obesity and ameliorating insulin resistance. Mechanistic studies demonstrate that IL-27 directly targets adipocytes, activating p38 MAPK-PGC-1α signalling and stimulating the production of UCP1. Notably, therapeutic administration of IL-27 ameliorated metabolic morbidities in well-established mouse models of obesity. Consistently, individuals with obesity show significantly decreased levels of serum IL-27, which can be restored after bariatric surgery. Collectively, these findings show that IL-27 has an important role in orchestrating metabolic programs, and is a highly promising target for anti-obesity immunotherapy.

Immunoregulatory Cells and Cytokines Discriminate Disease Activity Score 28-Remission Statuses and Ultrasound Grades in Rheumatoid Arthritis Patients with Non-High Disease Activity.

It is not clear whether immunoregulatory cytokines and cells are associated with Disease Activity Score 28 (DAS28) scores and ultrasound grades/scores. Here, we investigated the relationships between immunoregulatory cytokines or cells and different DAS28 scores or ultrasound grades/scores in patients with rheumatoid arthritis (RA). This study enrolled 50 RA patients (with 147 visits) who had remission/low/moderate DAS28-ESR scores (92% in remission and low disease activity) at baseline. Blood was collected and an ultrasound was performed three times in a year. Percentages of regulatory B cells and T regulatory type 1 cells and M2 macrophage numbers in the blood were examined. Plasma levels of 10 immunoregulatory cytokines IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-35, TGF-ß1, sTNF-R1, and sTNF-R2 and monocyte chemotactic protein-1 (MCP-1) were assessed using ELISA assay. The correlations of cytokines and cells with different DAS28 scores and ultrasound grades were investigated, and cytokines and cells were compared between different categories of DAS28 scores and ultrasound grades. Plasma TGF-ß1 levels were higher in the DAS28-ESR < 2.6 (remission) subgroup than in the DAS28-ESR ≥ 2.6 (nonremission) subgroup (p = 0.037). However, plasma TGF-ß1 levels were higher in the high ultrasound grade subgroup than those in the low ultrasound grade subgroup (p = 0.007). The number of M2 macrophages was lower in the DAS28-MCP-1 < 2.2 subgroup than in the DAS28-MCP-1 ≥ 2.2 subgroup (p = 0.036). The levels of TGF-ß1, sTNF-R2, IL-10, and IL-27 were higher in patients with high ultrasound grades than in those with low ultrasound grades. IL-27 was also higher in the nonremission DAS28-ESR subgroup than the remission one (p = 0.025). Moreover, sTNF-R1 levels in the 2011 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission subgroup were significantly lower than in the 2011 ACR/EULAR nonremission subgroup (p = 0.007). This trend was reflected in that lower sTNF-R1 levels correlated with low DAS28-MCP-1 scores (rho = 0.222, p = 0.007). We conclude that high plasma TGF-ß1 levels indicate the DAS28-ESR remission (<2.6) subgroup and the high ultrasound grade subgroup. IL-27 probably connects the nonremission DAS28-ESR to high ultrasound grades. Low sTNF-R1 levels probably link low DAS28-MCP-1 scores with the 2011 ACR/EULAR remission subgroup. It suggests that incongruent immuno-inflammatory abnormalities exist between DAS28 scores and ultrasound grades, and are also dissimilar among various DAS28-formula categories. Therefore, this study may provide a basis for further research into individual cytokines and immunoregulatory cells behind each DAS28 formula and ultrasound grades/scores.

Loss of IL-27Rα Results in Enhanced Tubulointerstitial Fibrosis Associated with Elevated Th17 Responses.

Clinical and experimental studies have established that immune cells such as alternatively activated (M2) macrophages and Th17 cells play a role in the progression of chronic kidney disease, but the endogenous pathways that limit these processes are not well understood. The cytokine IL-27 has been shown to limit immune-mediated pathology in other systems by effects on these cell types, but this has not been thoroughly investigated in the kidney. Unilateral ureteral obstruction was performed on wild-type and IL-27Rα-/- mice. After 2 wk, kidneys were extracted, and the degree of injury was measured by hydroxyproline assay and quantification of neutrophil gelatinase-associated lipocalin mRNA. Immune cell infiltrate was evaluated by immunohistochemistry and flow cytometry. An anti-IL-17A mAb was subsequently administered to IL-27Rα-/- mice every 2 d from day of surgery with evaluation as described after 2 wk. After unilateral ureteral obstruction, IL-27 deficiency resulted in increased tissue injury and collagen deposition associated with higher levels of chemokine mRNA and increased numbers of M2 macrophages. Loss of the IL-27Rα led to increased infiltration of activated CD4+ T cells that coproduced IL-17A and TNF-α, and blockade of IL-17A partially ameliorated kidney injury. Patients with chronic kidney disease had elevated serum levels of IL-27 and IL-17A, whereas expression of transcripts for the IL-27RA and the IL-17RA in the tubular epithelial cells of patients with renal fibrosis correlated with disease severity. These data suggest that endogenous IL-27 acts at several points in the inflammatory cascade to limit the magnitude of immune-mediated damage to the kidney.

Serum IL-27 predicts the severity and prognosis in patients with community-acquired pneumonia: a prospective cohort study.

Background: The previous studies have revealed that IL-27 was involved in the pathophysiology of pulmonary inflammatory diseases. However, the role of IL-27 in community-acquired pneumonia (CAP) was unclear. The goal of this research was to explore the associations of serum IL-27 with the severity and prognosis among CAP patients through a prospective cohort study. Methods: The whole of 239 healthy population and 239 CAP patients were enrolled. Fasting blood samples were collected. Inflammatory cytokines were detected using enzyme linked immunosorbent assay (ELISA). Demographic characteristics and clinical information were analyzed. Results: Serum IL-27 on admission was significantly risen in CAP patients compared with control subjects. Besides, serum IL-27 was gradually increased in line with CAP severity scores. Correlative analysis suggested that serum IL-27 was associated with blood routine indices, renal function, liver function, myocardial function and inflammatory cytokines. Linear and logistic regression analyses revealed that serum IL-27 was positively correlated with CAP severity scores. Logistic regression analysis demonstrated that serum higher IL-27 on admission elevated the risks of vasoactive agent usage and longer hospital stay during hospitalization among CAP patients. Conclusions: Serum IL-27 is markedly and positively associated with the severity and poor prognosis among CAP patients, indicating that IL-27 may involve in the pathophysiological process of CAP. Serum IL-27 may be used as a biomarker for diagnosis and prognosis in CAP patients.

The association of IL-3, IL-17A, and IL 27 serum levels with susceptibility to toxoplasmosis in recurrent abortion of Iraqi women.

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.

[A pilot study of plasma interleukin-6 and interleukin-27 in differential diagnosis of acute respiratory distress syndrome and neonatal respiratory distress syndrome in preterm infants]. / 血浆IL-6与IL-27åœ¨é‰´åˆ«æ—©äº§å„¿æ€¥æ€§å‘¼å¸çª˜è¿«ç»¼åˆå¾ä¸Žå‘¼å¸çª˜è¿«ç»¼åˆå¾çš„åˆæ­¥ç ”ç©¶.

OBJECTIVES: 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. METHODS: 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 (n=18) and NRDS group (n=20). ELISA was used to measure the plasma levels of IL-6 and IL-27. The receiver operating characteristic (ROC) curve was used to analyze the value of each index in the diagnosis of ARDS. RESULTS: The ARDS group had significantly higher plasma levels of IL-6 and IL-27 than the NRDS group (P<0.05). The ROC curve analysis showed that IL-6 had an area under the ROC curve (AUC) of 0.867 for the diagnosis of ARDS, with a sensitivity of 61.1% and a specificity of 95.0% at the cut-off value of 56.21 pg/mL. The ROC curve analysis also showed that IL-27 had an AUC of 0.881 for the diagnosis of ARDS, with a sensitivity of 83.3% and a specificity of 80.0% at the cut-off value of 135.8 pg/mL. CONCLUSIONS: Plasma IL-6 and IL-27 can be used as biological indicators for early differential diagnosis of ARDS and NRDS in preterm infants.

Serum levels of the IL-6 family of cytokines predict prognosis in renal cell carcinoma (RCC).

PURPOSE: An improved understanding of RCC immunology should shed further light on RCC tumor biology. Our objective was to study to what extent serum levels of the IL-6 family of cytokines at diagnosis were relevant to survival. METHODS: A total of 118 consecutively patients with RCC, in which the tumor was surgically removed at Haukeland University Hospital during the period from 2007 to 2010, were included. The patients were followed-up for 10 years. The morning before surgery blood was sampled and serum frozen, with levels of IL-6, IL-27, IL-31, OSM, CNTF, IL-6Rα and gp130 determined. RESULTS: Among patients with the highest quartile of IL-6 (> 8 pg/ml) (n = 29), six of nine who had metastasis at diagnosis had such high IL-6 values. Among presumed radically treated patients, a high IL-6 and IL-27 strongly predicted recurrence. In particular, the predictions among patients with large (diameter > 7 cm) tumors were excellent regarding both IL-6 and IL-27 values. High gp130 serum levels predicted an overall survival (OS) among RCC patients with large tumors. Patients with a high IL-6 exhibited a strong expression of IL-6 in endothelial- and vascular smooth muscle cells. Moreover, the level of intra-tumoral CD3-positive cells predicted survival. CONCLUSIONS: IL-6 and IL-27 seem to play a role in RCC biology. IL-6 enables the pinpointing of metastatic condition at diagnosis, as well as together with IL-27, the predicting of survival and recurrence. Endothelial cells and vascular smooth muscle cells are both suggested as important sources of IL-6.

Anti-inflammatory cytokines IL-27, IL-10, IL-1Ra and TGF-ß in subjects with increasing grades of glucose intolerence (DM-LTB-2).

Anti-inflammatory cytokines act as double edged swords- they can dampen inflammation but can also suppress immunity. The role played by these cytokines in latent TB infected (LTBI) subjects, with various grades of glucose intolerance was studied. Both serum levels and recall-secretion of IL-27, IL-10, IL-1Ra and TGF-ß in Normal Glucose Tolerance (NGT), Pre-Diabetes (PDM), Newly diagnosed Diabetes (NDM) and Known Diabetes (KDM) subjects, both with and without LTBI (n = 382), were quantified by ELISA. All the subjects were screened for LTBI by QuantiFERON-TB Gold test. Serum levels of IL-27, IL-10 and IL-1Ra were significantly elevated in the LTB-PDM, compared to LTB-NGT group. Increased IL-27 and IL-10 levels and decreased levels of TGF-ß were seen in the LTB-NDM, compared to LTB-NGT group. Decreased serum levels of IL-27 and increased levels of IL-1Ra and TGF-ß were seen in the LTB-KDM, compared to LTB-NGT group. TB antigens induced the secretion of IL-1Ra in LTB+ subjects in the NGT, PDM and NDM groups, but not in the KDM group. Co-morbidity with LTBI brought about (diabetic) stage-specific modulation, in these cytokine levels. Major defects in the circulating levels and recall secretion of anti-inflammatory cytokines, as seen in LTB+KDM subjects, could fuel DM-TB synergy.

Interleukin-17D Aggravates Sepsis by Inhibiting Macrophage Phagocytosis.

OBJECTIVES: Interleukin-17D has been shown to participate in the control of viral infections and cancer. Here we hypothesized that interleukin-17D may play a potential role in sepsis. DESIGN: Prospective randomized animal investigation and in vitro human blood studies. SETTING: Research laboratory from a university hospital. SUBJECTS: Female C57BL/6J mice, sepsis patients by Sepsis-3 definitions, ICU patient controls, and healthy individuals. INTERVENTIONS: Serum concentrations of interleukin-17D were measured and analyzed in human sepsis patients, patient controls, and healthy individuals. The contribution of interleukin-17D to sepsis-related survival, bacterial burden, and organ injury was assessed in a murine model of cecal ligation and puncture-induced polymicrobial sepsis by the use of anti-interleukin-17D antibody and recombinant interleukin-17D protein. The effects of interleukin-17D on bacterial phagocytosis by macrophages were also investigated using in vitro cell models. MEASUREMENTS AND MAIN RESULTS: On the day of ICU admission (day 0), septic patients had significantly higher serum concentrations of interleukin-17D than patient controls and healthy individuals. Serum interleukin-17D levels remained significantly elevated in septic patients from ICU admission to day 3 and correlated with Sequential (Sepsis-related) Organ Failure Assessment scores and documented bacteremia on day 0. Furthermore, nonsurvivors of septic patients displayed significantly higher interleukin-17D levels compared with survivors of septic patients on days 0 and 1 of ICU admission. In animal models of sepsis, treatment with anti-interleukin-17D antibody protected mice from cecal ligation and puncture-induced severe sepsis, which was associated with improved bacterial clearance and organ injury. Conversely, administration of recombinant interleukin-17D protein aggravated cecal ligation and puncture-induced nonsevere sepsis. Furthermore, we found that interleukin-17D impaired bacterial phagocytosis by macrophages. Phagocytosis inhibition by interleukin-17D involved its ability to down-regulate the activation of nuclear factor-κB signaling pathway in macrophages upon bacterial infection. CONCLUSIONS: This study indicates a previously undescribed role of interleukin-17D in sepsis and identifies a new target for antisepsis treatment.

IL-27 is elevated in sepsis with acute hepatic injury and promotes hepatic damage and inflammation in the CLP model.

BACKGROUND: Immuno-inflammation plays an important role in the pathophysiological process of sepsis-associated acute hepatic injury (AHI). Interleukin 27 (IL-27) is an important inflammatory regulator; however, its role in this condition is not clear. METHODS: The clinical data and IL-27 serum levels in sepsis patients with or without AHI were analysed. Classical caecal ligation puncture (CLP) models were established in wild-type (WT) and IL-27 receptor (WSX-1)-deficient (IL-27R-/-) mice. In addition, exogenous IL-27 was injected into these mice, and the levels of IL-27, IL-6, and tumour necrosis factor alpha (TNF-α) in the serum and liver were then measured by enzyme-linked immunoassay (ELISA), quantitative PCR, and Western blotting. The severity of liver damage was evaluated by haematoxylin and eosin staining of liver tissue, TUNEL assay and evaluation of alanine aminotransferase (ALT) and aspartate transaminase (AST) serum levels. Furthermore, the effects of IL-27 on the levels of phosphorylated c-Jun N-terminal kinase (JNK) in macrophages were assessed by Western blotting, and the effects of IL-27 on the expression of IL-6 and TNF-α in macrophages were assessed by ELISA. RESULTS: IL-27 was elevated in sepsis patients with acute hepatic injury, which correlated with the Acute Physiologic Assessment and Chronic Health Evaluation II (APACHEII) scores, Sequential Organ Failure Assessment (SOFA) scores, and procalcitonin, C-reactive protein, IL-6, and TNF-α expression. In the CLP-WT group, IL-27 was highly expressed in the serum and liver, which correlated with the elevated content of ALT, AST, TNF-α, IL-6, and p-JNK in the serum and liver and the pathological injury of the liver. In CLP-IL-27R-/- group, however, the levels of ALT, AST, TNF-α, IL-6, and p-JNK in the serum and liver and the pathological injury of the liver were decreased. Treatment with exogenous IL-27 led to a further increase in these cytokines in WT mice after CLP. IL-27 treatment and lipopolysaccharide stimulation in vitro increased the expression of p-JNK, IL-6, and TNF-α in macrophages, and these changes were decreased by a JNK signalling pathway inhibitor. CONCLUSION: IL-27 is elevated in sepsis patients, especially those with acute hepatic injury. In addition, IL-27 can promote inflammatory reactions in the CLP-induced hepatic injury mice model.

The Expression of IL-12 Family Members in Patients with Hypertension and Its Association with the Occurrence of Carotid Atherosclerosis.

BACKGROUND: The interleukin-12 (IL-12) family consists of four members, namely, IL-12, IL-23, IL-27, and IL-35. The aim of this study was to examine the expression of circulating IL-12, IL-23, IL-27, and IL-35 in hypertensive patients. METHODS: Blood samples were collected from hypertensive patients and nonhypertensive (control) subjects, and protein multifactorial monitor kits were used to measure the plasma IL-12, IL-23, IL-27, and IL-35 levels in each sample. In addition, all enrolled subjects underwent ambulatory blood pressure monitoring (ABPM) and vascular stiffness. RESULTS: Hypertensive patients exhibited higher IL-12, IL-23, and IL-27 levels and lower IL-35 levels than control subjects; IL-12, IL-23, and IL-27 levels were positively correlated with both systolic blood pressure (SBP) and diastolic blood pressure (DBP), while IL-35 levels were negatively correlated with SBP and DBP. IL-12, IL-23, and IL-27 levels gradually increased in patients with grade I, II, and III hypertension, while IL-35 levels gradually reduced. According to the ABPM results, hypertensive patients were divided into the dipper and nondipper hypertension groups; IL-12, IL-23, IL-27, and IL-35 levels showed no differences between the two groups, but IL-12, IL-23, and IL-27 levels in both groups increased compared with those in the control group, while IL-35 levels decreased. Additionally, the expression of these IL-12 family members was influenced by many clinical factors and was independently associated with the occurrence of carotid atherosclerotic plaques. CONCLUSIONS: The changes in IL-12, IL-23, IL-27, and IL-35 levels were not associated with the presence of the nondipper type but were closely associated with the development of carotid atherosclerotic plaque in hypertensive patients.

Evaluation of Clinical Periodontal Indices and Serum Interleukin-27 by One-stage Full-mouth Disinfection and Quadrant Scaling and Root Planing in Periodontitis.

INTRODUCTION: One-stage oral disinfection technique has been developed to prevent cross-contamination between the treated and untreated areas between treatment sessions. Considering the role of inflammatory mediators in periodontitis, this study has been designed to compare the effects of one-stage oral disinfection with quadrant scaling and root planing (Q-SRP) on serum interleukin-27 (IL-27) levels in patients with moderate-to-advanced periodontitis. MATERIALS AND METHODS: In this study, two groups were considered. One group was treated with one-stage full-mouth oral disinfection (FMD), while the other group was treated with Q-SRP. In each group, 20 patients with chronic periodontitis were randomly selected based on the inclusion criteria. To evaluate the periodontal status, the clinical parameters of bleeding on probing (BOP), clinical attachment level (CAL), and probing depth (PD) were measured before treatment as well as at 2- and 4-month intervals after treatment. At the same intervals, the immunological index of the study (serum IL-27) was measured by special laboratory kits. The data were analyzed using the Statistical Package for the Social Sciences, version 16 (SPSS 16) software. In this study, p-value < 0.05 was considered statistically significant. RESULTS: The results of this study indicate that there has been an elevation in the mean of serum IL-27 after treatment in both treatment groups. There is no significant difference between the levels of IL-27 in the FMD group during the study period (p = 0.20). All periodontal indices (BOP, CAL, and PD) show clinical improvement in each group (p < 0.001). However, no significant difference was observed in the improvement of periodontal indices of CAL and PD (p < 0.05). CONCLUSION: According to the findings of this study, it can be said that both FMD and Q-SRP improve the periodontal indices and increase the serum level of the inflammatory mediator IL-27 in patients with periodontitis. CLINICAL SIGNIFICANCE: Considering the benefits of the FMD method, such as patient and dentist comfort, systemic effects, and its cost-effectiveness, use of this method is suggested in patients suffering from periodontitis.

Increased interleukin-27 cytokine expression in the central nervous system of multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disorder characterized by chronic inflammation, demyelination, and neuronal damage. During autoimmunity, cytokines are important mediators of the inflammation. In this line, interleukin-27 (IL-27) modulates inflammation and can be produced directly at inflammatory sites such as in the joints during rheumatoid arthritis or in the central nervous system (CNS) during MS. While in animal models of MS, treatment with IL-27 decreases the disease severity, its role in humans is not clearly established and it is not known if IL-27 could be detected in the cerebrospinal fluid (CSF) of MS patients. METHODS: In this study, we measured IL-27 levels using a quantitative enzyme-linked immunosorbent assay in CSF of patients with relapsing remitting multiple sclerosis (RRMS), isolated optic neuritis (ON) and non-inflammatory neurological disease (NIND) as well as in the sera of healthy donors (HD) and RRMS patients undergoing different disease modifying treatments. We further confirmed by immunohistology of patient biopsies the identity of IL-27 producing cells in the brain of active MS lesions. RESULTS: We observed that IL-27 levels are increased in the CSF but not in the sera of RRMS compared to HD. We confirmed that IL-27 is expressed in active MS plaques by astrocytes of MS patients. CONCLUSIONS: Our results point toward a local secretion of IL-27 in the CNS that is increased during autoimmune processes. We propose that local production of IL-27 could sign the induction of a regulatory response that promotes inflammation's resolution. The effect of new immunomodulatory therapies on cerebral IL-27 production could be used to understand the biology of IL-27 in MS disease.

The role of interleukin-27 in predicting spontaneous HBeAg seroconversion in chronic hepatitis B infection.

BACKGROUND AND AIMS: Hepatitis B e seroconversion, associated with preceding hepatic inflammation, marks the transition from immune active to residual phase in the natural disease history of chronic hepatitis B. Recently, interleukin-27 has been reported to be associated with hepatic inflammation in hepatitis B infection. We aimed to evaluate the role of interleukin-27 in predicting spontaneous e seroconversion in chronic hepatitis B. METHODS: A total of 142 treatment-naive hepatitis B patients with positive e antigen were recruited. Interleukin-27, hepatitis B viral DNA levels and liver function parameters, were measured on presentation. Patients who had spontaneous e seroconversion within 3 years of follow-up were compared with those without e seroconversion within the same period of time. Factors predictive of spontaneous e seroconversion were identified. RESULTS: Of the 142 patients (M:F=80:62, median age: 31), 44 (31%) had spontaneous e seroconversion within 3 years of follow-up. Multivariate analyses revealed that younger age, lower viral DNA and lower interleukin-27 levels on presentation independently predicted spontaneous e seroconversion: the rate was significantly higher in patients aged <31 (OR: 11.022, 95% CI: 3.658-33.205; P<.001), viral DNA <5 log IU/mL (OR: 2.311, 95% CI: 1.049-5.091; P=.038) and interleukin-27 <67.3 pg/mL (OR: 3.276, 95% CI: 1.257-8.536; P=.015). Among patients with all these three favourable factors on presentation, 77% of them underwent spontaneous e seroconversion within 3 years. CONCLUSIONS: Low interleukin-27 levels were associated with early e seroconversion. The combination of baseline interleukin-27 <67.3 pg/mL and viral DNA <5 log IU/mL in young patients was useful for predicting early spontaneous e seroconversion in treatment-naïve chronic hepatitis B patients.

IL-27 plasma level in relapsing remitting multiple sclerosis subjects: The double-faced cytokine.

Interleukin-27 (IL-27) is a member of IL-6/IL-12 cytokine family which possesses pro- and anti-inflammatory properties and participates in the pathogenesis of various autoimmune diseases. In our case-control study, plasma was collected from healthy subjects as control group (n = 40) and patients with relapsing-remitting multiple sclerosis (RRMS) (n = 40), including new identified cases without treatment (n = 12) and those treated with Interferon beta (IFN-ß) (n = 28). The plasma level of IL-27 was assessed by ELISA method. Our results indicated that plasma level of IL-27 in MS patients increased significantly compared to the control subjects (P = 0.027). Furthermore, after parting case group into the two sub-groups, results revealed a significant difference of IL-27 plasma levels between control group and treated patients (P < 0.001), but not about that of between healthy subjects and untreated MS patients (P = 0.259). Also, mean levels of IL-27 in treated and untreated patients showed a significant difference (P = 0.007). These results demonstrate the possible modulation of IL-27 during autoimmune disease in human which may suggest the suppressive or therapeutic role of IL-27 on inflammatory diseases.

Polymorphisms and plasma levels of IL-27: impact on genetic susceptibility and clinical outcome of bladder cancer.

BACKGROUND: Interleukin-27 (IL-27) has been recognized as a pleiotropic cytokine with both pro- and anti-inflammatory properties. Few studies have investigated polymorphisms and serum/plasma levels of IL-27 in diseases including cancers. This study has analyzed the associations of IL-27 gene polymorphisms, as well as plasma levels of IL-27, with susceptibility to bladder cancer and clinical outcome. METHODS: Three hundred and thirty-two patients (nonmuscle-invasive bladder cancer (NMIBC)/muscle-invasive bladder cancer (MIBC): 176/156) included in a 60-month follow-up program and 499 controls were enrolled. Two single nucleotide polymorphisms (SNPs), rs153109 and rs17855750, were genotyped by polymerase chain reaction (PCR) -restriction fragment length polymorphism (RFLP) method. Plasma concentration of IL-27 was determined by ELISA in 124 patients (NMIBC/MIBC: 50/74) and 151 controls. RESULTS: Significantly increased risk for bladder cancer was associated with AG/GG genotypes of rs153109 (P = 0.029). No GG genotype of rs17855750 was observed in controls, while 4 patients were found to be GG homozygotes, suggesting GG genotype may be associated with bladder cancer risk (P = 0.006). For bladder cancer patients, SNP rs17855750 was also associated with increased risk for MIBC. For MIBC patients, but not NMIBC, TG/GG genotypes of rs17855750 turned out to be a protective factor for overall survival (P = 0.035). Significantly reduced plasma levels of IL-27 were observed in both NMIBC and MIBC patients compared with controls (P < 0.0001). CONCLUSION: Our data suggest that polymorphisms and reduced plasma levels of IL-27 may predict the susceptibility to bladder cancer, and rs17855750 may be a useful marker to distinguish patients with high risk of death.

IL-6, through p-STAT3 rather than p-STAT1, activates hepatocarcinogenesis and affects survival of hepatocellular carcinoma patients: a cohort study.

BACKGROUND: Biologic activities of functional mediators activate downstream transducers regulating inflammation and carcinogenesis. Correlation among mediators (IL-6, IL-27, TNF-α, and VEGF) with STAT proteins at diverse clinical-pathologic stages of hepatocellular carcinoma (HCC) remains limited. METHODS: Serum mediators assayed from 147 untreated HCC cases (HCC-total group) included 70 HBV-infected (HCC-HBV group), 64 HCV-infected (HCC-HCV group), and 13 without HBV-/HCV-infection (HCC-NBNC group). Another 156 non-HCC individuals comprised 54 healthy individuals (HG) and 102 chronic hepatitis patients (CH-total group) as control group. To correlate with serum mediators, 86-paired liver tissues (CH: 52 and HCC: 34 cases) served for p-STATs proteins immunostain. RESULTS: Although four mediators (IL-6, IL-27, TNF-α, and VEGF) significantly over-expressed, IL-6 presented the strongest correlation in HCC-total versus CH-total or HG groups (HCC-total versus CH-total: P < 0.001; HCC-total versus HG: P < 0.001). Over-expressed IL-6 concentration linked with poor liver function (Albumin: r = -0.383, P < 0.001; Bilirubin: r = 0.280, P = 0.001; INR: r = 0.299, P < 0.001; AST: 0.212, P = 0.016), tumor progression (TNM system: r = 0.370; P < 0.001), clinical condition severity (BCLC system: r = 0.471; P < 0.001; terminal- versus early-stage HCC, P = 0.001; advanced- versus early-stage HCC, P = 0.007; terminal- versus intermediate- stage HCC P = 0.003; advanced- versus intermediate-stage HCC P = 0.019), and 6-month mortality (P = 0.024). Likewise, serum IL-6 (r = 0.501, P = 0.003) as compared to IL-27 (r = 0.052, P = 0.770), TNF-α (r = 0.019, P = 0.917), and VEGF (r = 0.096, P = 0.595) expression reflected positive correlation with activation of tissues p-STAT3 rather than p-STAT1. CONCLUSIONS: Serum IL-6, through p-STAT3 rather than p-STAT1 signal pathway, affected hepatic function, tumor progression, and determine HCC patient survival.

Decreased IL-27 Negatively Correlated with Th17 Cells in Non-Small-Cell Lung Cancer Patients.

The presence of Th17 cells and IL-27 is observed in a variety of inflammatory associated cancers. However, there are some data on the role of Th17 cells and IL-27 in the regulation of immune reactions in non-small-cell lung cancer (NSCLC). The aim of this study is to assess the variation of Th17 cells and IL-27 in the peripheral blood (PB) of patients with NSCLC. The proportion of Th17 cells in peripheral blood mononuclear cells (PBMCs) was evaluated by flow cytometry. The serum concentrations of IL-27 and IL-17 were measured by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of RORγt and IL-27 in the peripheral blood was examined by real-time quantitative polymerase chain reaction (QPCR). Expression of IL-27 was lower in NSCLC patients compared with normal controls. The frequency of Th17 cells was increased in NSCLC patients, accompanied by the upregulation of IL-17 and RORγt. IL-27 negatively correlated with the number of Th17 cells and the RORγt mRNA. Our results indicate that IL-27 might inhibit Th17 differentiation in NSCLC patients and better understanding of the regulatory effects of IL-27 on Th17 cells may shed light on potential new targets in cancer prevention and therapy.

Human interleukin-27: wide individual variation in plasma levels and complex inter-relationships with interleukin-17A.

Although it is widely believed that interleukin (IL)-27 is anti-inflammatory, its role in controlling human immune responses is not fully established. In particular, its interactions with T helper type 17 (Th)17 cytokines are unclear. Our aims were to establish the relationships between IL-27 and proinflammatory cytokines, including IL-17A, in human sera and cultures of peripheral blood mononuclear cells. Plasma IL-27 levels in 879 healthy humans from 163 families varied widely, but with relatively low heritability (19%). Despite IL-27 including a subunit encoded by Epstein-Barr virus-induced gene 3 (EBI3), there was no correlation of levels with serological evidence of infection with the virus. Although IL-27 has been reported to inhibit IL-17A production, we demonstrated a strong positive correlation in sera, but lower correlations of IL-27 with other proinflammatory cytokines. We verified that IL-27 inhibited IL-17A production by human peripheral blood T cells in vitro, but not that it stimulated IL-10 secretion. Importantly, addition of IL-17A decreased IL-27 production by stimulated T cells but had the opposite effect on resting T cells. Together, these data suggest a model whereby IL-27 and IL-17A exerts complex reciprocal effects to boost inflammatory responses, but restrain resting cells to prevent inappropriate activation.

Increased interleukin-27 promotes Th1 differentiation in patients with chronic immune thrombocytopenia.

Chronic immune thrombocytopenia (cITP) is an autoimmune disease with disturbed cytokine profile. Although plasma levels of IL-27 are shown to be associated with cITP, its association with T cell subsets has not been studied. The objective of this study was to study the association between IL-27 and different T cell subsets in patients with cITP. Heparinized blood was collected from 31 patients with cITP and 36 healthy controls (platelet count <100 × 10(9)/l and 103-280 × 10(9)/l, respectively). The percentage of Th1, Th2 and Th17 cells in peripheral blood mononuclear cells (PBMCs) were enumerated by flow cytometry, and the mRNA levels of IL-27, T-bet, GATA-3 and retinoid-related orphan receptor gamma (RORγt) by real-time reverse transcriptase polymerase chain (RT-PCR). Plasma cytokine levels of IL-27, interferon-gamma (IFN-γ), IL-4 and IL-17A were estimated by flow cytometrix. The effect of exogenous recombinant IL-27(rhIL-27) on the differentiation of T cells into Th1, Th2 and Th17 cells was investigated by cell culture. The percentage of Th1 and Th17 cells and the plasma concentration and mRNA levels of IL-27 were significantly higher in cITP patients compared with healthy controls. Plasma levels of IL-27 correlated positively with percentage of Th1 cells in patients with cITP. Exogenous (rhIL-27) could significantly up-regulate the percentage of Th1 cells and down-regulate Th2 cells in vitro. Th17 cells were reduced in the presence of (rhIL-27) in controls but had no effect in patients with cITP. The up-regulation of IL-27 might cause Th1 differentiation and might be involved in the pathophysiology of cITP.