Serum IL-18 Levels Research Articles

Interleukin-18 in Brazilian Rheumatoid Arthritis Patients: Can Leflunomide Reduce It?

Objectives Rheumatoid arthritis affects about 1% of the world's population. This is a chronic autoimmune disease. It is predominant in females with progressive joint damage. Immune cells are involved, especially Th1/Th17 lymphocytes and their inflammatory cytokines. These proteins have different functions in the immune system, such as IL-16 is a chemotactic factor; IL-18 can activate NFκB transcription producing inflammatory proteins; IL-31 can activate the JAK/STAT pathway which leads to the production of inflammatory factors in chronic diseases; IL-33 promotes IL-16 secretion which causes lymphocyte recruitment, and IL-32 and IL-34 appear to increase TNF secretion by macrophages activation in AR. The aim of this study was to evaluate serum levels of IL-16, IL-18, IL-31, IL-32, IL-33, and IL-34 and compare them with the severity and treatment of RA patients if there are any correlations. Methods A total of 140 RA patients and 40 healthy donors were recruited from the Department of Rheumatology at Hospital das Clínicas from the Federal University of Pernambuco. 60 AR patients were naïve for any treatment. Serum cytokine levels were determined using an ELISA kit. Results Serum IL-16 (p = 0.0491), IL-18 (p < 0.0001), IL-31 (p = 0.0004), and IL-32 (p = 0.0040) levels were significantly increased in RA patients compared with healthy donors. It was observed that patients using leflunomide had the lowest IL-18 levels, close to controls levels (p = 0.0064). Conclusion IL-16, IL-18, IL-31, and IL-32 are increased in the serum of RA patients. IL-18 is at lower levels in those AR who are taking leflunomide as treatment.

Therapeutic effects of melatonin on an ovalbumin-induced allergic rhinitis model in rats

ObjectiveWe aimed to investigate the therapeutic effects of melatonin in an experimental AR model. MethodsThirty-two Wistar rats were randomised into four groups (n = 8 each). The experimental AR model was established in the saline (SF), ethanol, and melatonin groups via intraperitoneal (i.p.) injections and intranasal application of ovalbumin. The SF, ethanol, and melatonin groups received daily i.p. saline, 2% ethanol dissolved in saline, and 10 mg/kg melatonin dissolved in 2% ethanol and saline. The control group received the same amount of i.p. and intranasal saline. Total nasal symptom scores were recorded in all rats on days 1 (baseline), 15, 20, 25, and 30. Serum ovalbumin-specific IgE, IL-13, and melatonin levels were measured on days 1 (baseline), 15, and 30. The nasal mucosa of all rats was scored histopathologically. ResultsThe total nasal symptom scores and serum ovalbumin-specific IgE values of the SF, ethanol, and melatonin groups were significantly higher on day 15 than those of the control group. On day 30, the scores and serum ovalbumin-specific IgE values of the melatonin group were similar to those of the control, whereas the SF and ethanol groups had statistically higher scores. The histological scores of the SF and ethanol groups were significantly higher than those of the control and melatonin groups, but no significant difference was found between the melatonin and control groups. ConclusionMelatonin reduced total nasal symptom scores and serum ovalbumin-specific IgE levels and improved histological inflammation parameters in the ovalbumin-induced rat experimental AR model.

Increased Peripheral TFH Cells and Serum Interleukin-21 in Childhood Mycoplasma Pneumoniae Pneumonia.

The aim of this study was to investigate the role of TFH cells and interleukin (IL)-21 in the pathogenesis of childhood Mycoplasma pneumoniae pneumonia (MPP). It was a retrospective study carried out at Yantai Yuhuangding Hospital, China from July 2016 to June 2019. It comprised 46 healthy control (HC) children and 106 pediatric patients, including 60 children with general MPP (GMPP) and 46 children with refractory MPP (RMPP). Flow cytometry was used to detect the frequencies of peripheral TFH cells. The levels of serum IL-21 were tested by ELISA. The transcriptional factors Bcl-6 and Blimp-1 mRNA levels were examined using RT-qPCR. The percentage of TFH cells and expression levels of IL-21 and Bcl-6 in peripheral blood were all significantly elevated in MPP groups compared with HC group (all p <0.001). Furthermore, it was found that a significantly higher percentage of TFH cells and levels of IL-21 and Bcl-6 in RMPP children, compared with GMPP children (all p <0.05). In contrast, lower Blimp-1 levels were observed in MPP groups (p <0.001), especially in RMPP group (p = 0.021). Therefore, the elevated expansion of TFH cells and the increased secretion of IL-21 cytokine may contribute to the pathogenesis of childhood MPP, while its excessive response may be associated with the development of childhood RMPP. Key Words: TFH cells, IL-21, Children, Mycoplasma pneumoniae pneumonia.

CARD8 SNP rs11672725 Identified as a Potential Genetic Variant for Adult-Onset Still's Disease.

Adult-onset Still’s disease (AOSD), an autoinflammatory disorder, is related to the dysregulation of NLR3-containing a pyrin domain (NLRP3)-inflammasome signaling. We aimed to investigate the associations of genetic polymorphisms of NLRP3-inflammasome signaling with AOSD susceptibility and outcome and to examine their functional property. Fifty-three candidate single-nucleotide polymorphisms (SNPs) involved in NLRP3-inflammasome response were genotyped using Sequenom MassArray on the samples from 66 AOSD patients and 128 healthy controls. The significant SNPs were validated by direct sequencing using a TaqMan SNP analyzer. Serum levels of associated gene products were examined by ELISA. One SNP rs11672725 of CARD8 gene was identified to be significantly associated with AOSD susceptibility by using MassArray and subsequent replication validation (p = 3.57 × 10−7; odds ratio 3.02). Functional assays showed that serum CARD8 levels were significantly lower in AOSD patients (median, 10,524.6 pg/mL) compared to controls (13,964.1 pg/mL, p = 0.005), while levels of caspase-1, IL-1β and IL-18 were significantly higher in patients (107.1 pg/mL, 2.1 pg/mL, and 1495.8 pg/mL, respectively) than those in controls (99.0 pg/mL, 1.0 pg/mL, and 141.4 pg/mL, respectively). Patients carrying rs11672725CC genotype had significantly higher serum caspase-1 and IL-18 levels (121.3 pg/mL and 1748.6 pg/mL) compared to those with CT/TT genotypes (72.6 pg/mL, p = 0.019 and 609.3 pg/mL, p = 0.046). A higher proportion of patients with rs11672725CC genotype had a systemic pattern of disease outcome, which was linked to low CARD8 levels. A novel variant, rs11672725, of the CARD8 gene was identified as a potential genetic risk for AOSD. Patients carrying the rs11672725CC genotype and C allele had low CARD8 levels, and were predisposed to a systemic pattern with an elevated expression of inflammasome signaling.

Anti-pruritic effect of nemolizumab in hemodialysis patients with uremic pruritus: a phase II, randomized, double-blind, placebo-controlled clinical study

BackgroundThe pathophysiology of uremic pruritus (UP), which is characterized by systemic and intractable itching, remains unclear. As interleukin (IL)-31 may be involved, we conducted a phase II, randomized, controlled study to evaluate nemolizumab (anti-IL-31 receptor A antibody) in Japanese hemodialysis patients with UP.MethodsPatients were randomly assigned (1:1:1:1:1) to one of four double-blind groups (receiving a single subcutaneous injection of nemolizumab 0.125, 0.5, or 2.0 mg/kg, or placebo on Day 1) or an open-label reference group (receiving oral nalfurafine hydrochloride 2.5–5 μg once daily for 12 weeks). The primary endpoint was the difference in the absolute change in pruritus visual analog scale (VAS) at Week 4 between placebo and each nemolizumab group.ResultsThe primary efficacy endpoint was not met. The mean change from baseline with all three nemolizumab doses at Week 1, and with 0.5 mg/kg at Week 4, was greater than with placebo. Least square mean differences (95% confidence intervals) in the absolute changes between the placebo arm and each nemolizumab arm were − 2.4 (− 19.7, 14.9) for 0.125 mg/kg, − 8.7 (− 26.6, 9.2) for 0.5 mg/kg, and 0.4 (− 17.0, 17.8) for 2.0 mg/kg. Secondary efficacy parameters including the Shiratori severity score and 5-D itch score failed to show between-group differences. Patients with higher serum IL-31 levels at screening tended to have greater pruritus VAS reductions following nemolizumab treatment.ConclusionsIn this phase II study in patients with UP, the primary efficacy parameter was not met. Nemolizumab was generally well tolerated with no clinically significant safety concerns.Clinical trial registrationJAPIC: JapicCTI-152961, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-152961.

Serum IP-10 and IL-7 levels are associated with disease severity of coronavirus disease 2019

We quantified the serum levels of 34 cytokines/chemokines in 30 patients with SARS-CoV-2 infection. Elevated levels of IP-10 and IL-7 were detected in the acute and convalescent stages of the infection and were highly associated with disease severity.

Modulation of Liver Inflammation and Fibrosis by Interleukin-37.

Background and Aims: Chronic inflammation induces liver fibrosis, cirrhosis and potentially liver cancer. Kupffer cells modulate hepatic stellate cells by secreting immunologically active proteins as TGF-β. TGF-β promotes liver fibrosis via the activation of Sma- and Mad-related protein 3. IL-37 broadly suppresses innate and adaptive immune responses. Intracellular IL-37 interacts with Smad3. We hypothesize that IL-37 downregulates the activation of hepatic Kupffer and stellate cells and interferes with the TGF-β signaling cascade to modulate liver fibrogenesis.Methods: The role of IL-37 on liver inflammation and fibrogenesis was assessed in three mouse models as well as isolated Kupffer- and stellate cells. Serum IL-37 was tested by ELISA in a clinical cohort and correlated with liver disease severity.Results: Transgene expression of IL-37 in mice extends survival, reduces hepatic damage, expression of early markers of fibrosis and histologically assessed liver fibrosis after bile duct ligation. IL-37tg mice were protected against CCl4-induced liver inflammation. Colitis-associated liver inflammation and fibrosis was less severe in IL-10 knockout IL-37tg mice. Spontaneous and LPS/TGF-β-induced cytokine release and profibrogenic gene expression was lower in HSC and KC isolated from IL-37tg mice and IL-37 overexpressing, IL-1β stimulated human LX-2 stellate cells. However, administration of recombinant human IL-37 did not modulate fibrosis pathways after BDL in mice, LX2 cells or murine HSCs. In a large clinical cohort, we observed a positive correlation of serum IL-37 levels with disease severity in liver cirrhosis.Conclusions: Predominantly intracellular IL-37 downregulates liver inflammation and fibrosis. The correlation of serum IL-37 with disease severity in cirrhosis suggests its potential as a novel target modulating the course of liver fibrosis.

Identification of serum interleukin-13 and interleukin-13 receptor subunit expressions: Rheumatoid arthritis-associated interstitial lung disease.

To identify the role of serum IL-13, and its receptor subunit expressions as a serologic marker of rheumatoid arthritis (RA)-associated ILD (RA-ILD). Fifty RA patients with ILD and 50 RA patients without ILD were examined, in addition to 50 controls. Disease Activity Score in 28 joints (DAS-28), the Health Assessment Questionnaire (HAQ), and medication history were evaluated. ESR, CRP, RF, Anti-CCP, Serum Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D) levels, Interleukin 13 and its receptors (IL-13 Rα1 and L-13 Rα2), and mRNA relative expression levels in peripheral blood mononuclear cells (PBMCs) were measured. High-resolution computed tomography (HRCT) scores were used with all RA patients with interstitial lung disease. Mean age, percent of male affection, duration of the disease, DAS28 and MHAQ were significantly higher in the RA-ILD group than in the RA-no ILD group. ESR, CRP, RF, anti-CCP, serum KL-6, SP-D, IL-13 levels, IL-13 Rα1and IL-13 Rα2 mRNA expressions were significantly increased in RA patients compared to controls; in addition, their levels were significantly higher in the RA-ILD group than in the RA-no ILD group. Serum IL-13 levels and IL-13 Rα1and IL-13 Rα2 were positively correlated with RF, Anti-CCP, KL-6, SP-D, and the HRCT score (P<.001). Serum IL-13 and its receptor subunit expressions are useful biomarkers which can be used in detecting severity of the interstitial lung disease in RA patients.

BXCL701, first-in-class oral activator of systemic innate immunity pathway, combined with pembrolizumab (Keytruda) in men with metastatic castration-resistant prostate cancer (mCRPC).

124 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP), primarily DPP8 and DPP9, triggers inflammasome mediated pyroptosis in macrophages, leading to induction of IL-18 and IL-1ß, bridging between innate and adaptive immunity. PD-L1 expression correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor growth inhibition was observed with BXCL701 plus checkpoint inhibition. In a prior clinical study, single-agent BXCL701 resulted in objective responses in patients with Stage IV melanoma (unpublished). Methods: Eligible patients included in Phase 1b portion of this multicenter study, had progressing mCRPC (PCWG3), ≥1 prior systemic therapy, ≤2 lines of cytotoxic chemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anticancer therapy. In Phase 2 portion, patients with adenocarcinoma must have received 1 or 2 2nd generation androgen signaling inhibitors; patients with SCNC/t-NEPC must have received ≥1 prior line of chemotherapy. Patients received fixed-dose pembrolizumab (200 mg IV q21-days) with BXCL701 on days 1-14 at recommended Phase 2 dose (RP2D)/schedule. Primary endpoint is Composite Response (RECIST 1.1, PSA, CTC). Change in relevant immune effector cells was also evaluated. Results: In Phase 1b portion 13 patients were treated with BXCL701 in 3 cohorts: 0.4 mg qd (n = 3); 0.6 mg qd (n = 3) and 0.6 mg split dose (n=7). 7 patients had adenocarcinoma, 6 had small cell/neuroendocrine prostate cancer phenotype. Prior treatment included androgen deprivation therapy (n = 10), 2nd-generation androgen signaling inhibitors (n = 9), chemotherapy (n = 11), radiation therapy (n = 11). On-target adverse events (AEs) consistent with cytokine activation were seen at highest dose levels. In 0.6 mg qd cohort, all patients had events consistent with cytokine release syndrome: 3/3 had hypotension, including 1 grade 3 syncope—dose-limiting toxicity (DLT)—and 2 patients each had dizziness and lower extremity edema. Splitting 0.6 mg dose improved tolerability while maintaining total daily dose (TDD) previously associated with objective response; 3/7 patients had fatigue, and 1 patient each had low grade hypotension, dyspnea, chills, myalgia. Preliminary anti-tumor activity was seen with 1 patient achieving a PSA response and 4 patients with RECIST1.1 stable disease. Consistent dose and time dependent increases in serum IL-18 levels were observed. Conclusions: BXCL701 0.3 mg BID (0.6mg TDD) administered on days 1-14 was identified as RP2D when administered with pembrolizumab 200 mg every 21 days. Splitting TDD was associated with improved tolerability as evidenced by no reported DLTs and lower rates of other AEs of interest e.g. hypotension and peripheral edema. Preliminary data from Phase 2 portion will be presented. Clinical trial information: NCT03910660.

Mono-(2-ethylhexyl) phthalate Promotes Dengue Virus Infection by Decreasing IL-23-Mediated Antiviral Responses.

Exposure to environmental hormones such as di(2-ethylhexyl) phthalate (DEHP) has become a critical human health issue globally. This study aimed to investigate the correlations between DEHP/mono-(2-ethylhexyl) phthalate (MEHP) levels and macrophage-associated immune responses and clinical manifestations in dengue virus (DV)-infected patients. Among 89 DV-infected patients, those with DV infection-related gastrointestinal (GI) bleeding (n = 13, 15% of patients) had significantly higher DEHP exposure than those without GI bleeding (n = 76, 85% of patients), which were 114.2 ng/ml versus 52.5 ng/ml ΣDEHP in urine; p = 0.023). In an in vitro study using cultured human monocyte-derived macrophages (MDMs) to investigate the effects of MEHP, treatment increased IL-1β and TNF-α release but decreased IL-23 release, with negative correlations observed between urine ΣDEHP and serum IL-23 levels in patients. MEHP-treated MDMs had lower antiviral Th17 response induction activity in mixed T-cell response tests. The in vitro data showed that MEHP increased DV viral load and decreased IL-23 release dose-dependently, and adding IL-23 to MEHP-exposed MDMs significantly reduced the DV viral load. MEHP also suppressed IL-23 expression via the peroxisome proliferator-activated receptor-gamma (PPAR-γ) pathway. Further, the PPAR-γ antagonist GW9662 significantly reversed MEHP-induced IL-23 suppression and reduced the DV viral load. These study findings help to explain the associations between high MEHP levels and the high global burden of dengue disease.

Elevated serum gasdermin D N-terminal implicates monocyte and macrophage pyroptosis in adult-onset Still's disease.

Elevation of serum IL-18 in adult-onset Still's disease (AOSD) and systemic JIA (sJIA) suggests the role of the inflammasome in these diseases. Gasdermin D is a pore-forming protein playing central roles in inflammasome-mediated inflammation, but its role in rheumatic disease is unknown. We aimed to elucidate the auto-inflammatory mechanisms in AOSD and sJIA. Patients with AOSD, sJIA, hemophagocytic lymphohistiocytosis (HLH) and Behçet's disease followed at Yokohama City University (YCU), or US National Institutes of Health (NIH) were included in the study. Disease activity was evaluated by the modified Pouchot score. Ferritin and N-terminal gasdermin D levels in serum and culture supernatant were measured by ELISA. Primary monocytes (Mo) were stimulated with GM-CSF or M-CSF and differentiated into M1 macrophages (Mφ) or M2Mφ, respectively. The number of Mo/Mφ and their viability were monitored over time. Patients with active AOSD and sJIA had increased levels of serum gasdermin D N-terminal, which correlated with serum ferritin and IL-18 levels. Mo-derived Mφ from active AOSD patients showed reduced cell viability and increased cell death. The number of cultured Mφ cells on day nine was negatively correlated with the serum ferritin and gasdermin D levels. Higher ferritin and gasdermin D levels were observed in the M1Mφ culture supernatant of active AOSD patients. Gasdermin D inhibitors reduced the pyroptosis-mediated ferritin release in Mo. Elevation of serum gasdermin D N-terminal provides evidence for inflammasome activation triggering gasdermin D-mediated Mo and Mφ pyroptosis in AOSD and possibly sJIA.

Serum IL27 in Relation to Risk of Hepatocellular Carcinoma in Two Nested Case-Control Studies.

IL27 mRNA is highly enriched in the tissue of hepatocellular carcinoma. Overexpression of IL27 gene has been found to increase T-cell expression of inhibitory receptors, an immunosuppressive feature in tumor microenvironment, that promotes the development of hepatocellular carcinoma. Two parallel case-control studies of hepatocellular carcinoma, each with 100 case-control pairs were conducted in the Singapore Chinese Health Study and the Shanghai Cohort Study to examine the association between serum IL27 levels and risk of developing hepatocellular carcinoma. The IL27 concentrations were significantly elevated in sera collected from study participants 4 to 5 years prior to the diagnosis of hepatocellular carcinoma in both cohort studies. Compared with the lowest tertile of IL27, odds ratios (OR) of hepatocellular carcinoma for the highest tertile of IL27 was 46.08 [95% confidence interval (CI), 4.68-453.86] in the Singapore Chinese Health Study and 19.09 (95% CI, 3.81-95.57) in the Shanghai Cohort Study (both P trend <0.001). The corresponding ORs in both cohort studies were 42.47 (95% CI, 8.30-217.40) among individuals negative for hepatitis B surface antigen (HBsAg) and 242.46 (95% CI, 38.42-1,529.01) among those positive for HBsAg compared with the lowest tertile of interleukin-27 and negative HBsAg. Levels of IL27 in prediagnostic sera were significantly associated with increased risk of hepatocellular carcinoma development. IL27, through its immunosuppressive property, may play a significant role in the development of hepatocellular carcinoma. Serum levels of IL27 may be used as a biomarker for prediction of hepatocellular carcinoma development.

Efficacy of Tezepelumab in Patients with Severe, Uncontrolled Asthma with and without Nasal Polyposis: A Post Hoc Analysis of the Phase 2b PATHWAY Study

BackgroundTezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial cytokine implicated in asthma pathogenesis, from binding to its heterodimeric receptor. In the phase 2b PATHWAY study, tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo, irrespective of baseline disease characteristics, and improved lung function and symptom control, in adults with severe, uncontrolled asthma. This post hoc analysis assessed the efficacy of tezepelumab in adults with severe, uncontrolled asthma with and without nasal polyposis (NP).MethodsIn this post hoc analysis of the PATHWAY study (NCT02054130), participants (N=550) were randomized 1:1:1:1 to receive subcutaneous tezepelumab 70 mg every 4 weeks (Q4W), 210 mg Q4W or 280 mg every 2 weeks (Q2W), or placebo Q2W, for 52 weeks. The AAER over 52 weeks and the change from baseline to week 52 in blood eosinophil count, fractional exhaled nitric oxide (FeNO) levels and serum levels of interleukin (IL)-5 and IL-13 with tezepelumab 210 mg (the phase 3 dose) and placebo were analyzed in patients grouped by self-reported presence (NP+) or absence (NP−) of NP at screening.ResultsAt baseline, NP+ patients had higher blood eosinophil counts, higher FeNO levels and higher serum IL-5 and IL-13 levels than NP− patients. Tezepelumab 210 mg reduced the AAER versus placebo to a similar extent in both NP+ and NP− patients (NP+, 75% [95% confidence interval (CI): 15, 93], n=23; NP−, 73% [95% CI: 47, 86], n=112). Patients treated with tezepelumab 210 mg demonstrated greater reductions in blood eosinophil count and levels of FeNO, IL-5 and IL-13 than placebo-treated patients, irrespective of NP status.DiscussionTezepelumab reduced exacerbations and reduced type 2 inflammatory biomarkers in patients with and those without NP, supporting its efficacy in a broad population of patients with severe asthma.

Gadolinium Chloride Inhibits the Production of Liver Interleukin-27 and Mitigates Liver Injury in the CLP Mouse Model.

Background Liver macrophages play an important regulatory role in the inflammatory response of liver injury after severe infection. Interleukin- (IL-) 27 is an inflammatory cytokine that plays an important role in diseases caused by bacterial infection. However, the relationship between IL-27 and liver macrophages in liver injury after severe infection is not yet clear. Methods A cecal ligation puncture (CLP) model was established in wild-type (WT) and IL-27 receptor- (WSX-1-) deficient (IL-27r−/−) mice, and recombinant IL-27 and gadolinium chloride (GdCl3) were injected into WT mice in the designated groups. The serum and liver IL-27, IL-6, tumor necrosis factor alpha (TNF-α), and IL-1β expression levels were evaluated by ELISA, quantitative PCR, or Western blotting; serum ALT and AST were detected by detection kits; and the severity of liver damage was evaluated by hematoxylin and eosin staining and the TUNEL assay of the liver tissue from the different groups. Liver macrophage polarization was evaluated by immunofluorescence. In addition, the polarization of peritoneal macrophage was evaluated by flow cytometry. Results The serum and liver IL-27 expression levels were elevated in WT mice after CLP-induced severe infection, which were consistent with the changes in HE scores in the liver tissue. The levels of serum ALT, AST, liver IL-6, TNF-α, and IL-1β mRNA and liver pathological injury scores were further increased when pretreated with recombinant IL-27 in WT mice, but these levels were decreased in IL-27r−/− mice after CLP-induced severe infection compared to WT mice. In WT mice pretreated with GdCl3, liver pathological scores, serum ALT and AST, TUNEL-positive cell proportion from liver tissues, liver IL-27 expression, and the liver macrophages M1 polarization proportion decreased after CLP; however, the serum IL-27, IL-6, TNF-α, and IL-1β levels and the pathological lung and kidney scores were not significantly changed. When supplemented with exogenous IL-27, the liver pathological scores, serum ALT, AST, TUNEL-positive cell proportion of liver tissues, liver IL-27 expression, and the liver macrophage M1 polarization proportion increased. The in vitro, IL-27 expression increased in peritoneal macrophages when stimulated with LPS. Recombinant IL-27 together with LPS promoted the elevations in IL-6, TNF-α, and IL-1β levels in supernatant and the M1 polarization of peritoneal macrophages. Conclusion IL-27 is an important cytokine in the inflammatory response to liver injury after severe infection. The reduction of liver injury by gadolinium chloride in severe infection mice models may relate to the inhibition of liver IL-27 production. These changes may be mainly related to the decrease of liver macrophages M1 polarization. IL-27 may have a positive feedback on these macrophages.

Effect of acupuncture on hippocampal inflammation in rats with intrauterine distress induced hypoxic-ischemic brain injury

To observe the effects of acupuncture on the behavior, serum inflammatory cytokines, hippocampal Nod-like receptor protein 3(NLRP3) inflammasome-related proteins and microglia activation in rats with intrauterine distress induced ischemia-hypoxic brain injury (HIBD), so as to explore the mechanism of acupuncture underlying treatment of HIBD by regulating hippocampal inflammation. The HIBD model was established by clipping bilateral uterine arteries for 10 min and delaying caesarean delivery. HIBD rats were randomly divided into model group and acupuncture group according to body weight and litter factors, with 12 rats in each group. Twelve rats delivered normally were regarded as the normal group. Acupuncture was applied to bilateral "Benshen"(GB13) for 10 min, once a day for 14 consecutive days. H.E. staining was used to observe the pathological changes of hippocampus. The three chamber sociability test was used to determine the rat's social ability. The serum IL-1β and IL-18 levels, the hippocampal expressions of NLRP3, apoptosis associated speck like protein containing CARD(ASC) and cysteinyl aspartate specific proteinase-1(Caspase-1), andionized calcium bindingadaptor molecule-1(IBA-1) were detected by ELISA，Western blot and Immunofluorescence, separately. Compared with the normal group, The hippocampal neurons in the model group are arranged loosely, and the cells are solidified and shrunk and the whole cells are deeply stained. The time of exploring the stranger rat in the model group was significantly reduced (P<0.01). The contents of IL-1β and IL-18, the expressions of NLRP3, ASC, Caspase-1 and IBA-1 of the model group were higher than those of the normal group (P<0.01, P<0.05, P<0.001). Following acupuncture intervention, the cell structure of hippocampal neurons was improved, and there were fewer cases of cell solidification, atrophy, and deep staining. In comparison with the model group, the time of exploring stranger rat in the acupuncture group was significantly increased (P<0.01). The contents of IL-1β and IL-18, the expressions of NLRP3, ASC and Caspase-1, and IBA-1 of the acupuncture group were significantly down-regulated than those of the model group (P<0.01, P<0.05). Acupuncture can effectively improve the social behavior deficits of HIBD rats，which may be related to inhibition of the expression of inflammatory response proteins NLRP3, ASC and Caspase-1 in the hippocampus, decrease the activation of microglia in the hippocampus, and reduce serum IL-1β and IL-18, thereby alleviating inflammation.

Increased serum IL-27 concentrations and IL-27-producing cells in MG patients with positive AChR-Ab

ObjectiveThis study aims to explore the serum levels of IL-27 and the percentages of IL-27-producing cells in MG patients with positive acetylcholine receptor antibody (AChR-MG). MethodsA total of 17 AChR-MG patients and 22 sex- and age- matched healthy controls (HCs) were recruited. Serum IL-27 levels were determined by enzyme linked immunosorbent assay. The percentages of IL-27+ cells, IL-27-producing T (CD3+IL-27+) cells, and IL-27-producing B (CD19+IL-27+) cells were measured by flow cytometry. ResultsSerum IL-27 levels in AChR-MG were significantly higher than those in HCs (13.44 ± 0.89 vs 7.14 ± 0.75 pg/mL, P < 0.0001), and were decreased after intravenous immunoglobulin (IVIG) treatment (P = 0.004). Moreover, the frequencies of IL-27+ lymphocytes were significantly elevated in AChR-MG patients than those in HCs (P = 0.011), and were decreased after IVIG treatment (P = 0.014). Furthermore, the frequencies of IL-27-producing T cells (P = 0.017) and IL-27-producing B cells (P = 0.015) were significantly elevated in AChR-MG patients as compared to those in HCs. Meanwhile, we observed positive correlations between the frequencies of IL-27+ lymphocytes and MG-ADL score (P = 0.030, r = 0.527). By contrast, no significant correlation was found between IL and 27 serum levels and MG-ADL score (P = 0.099, r = −0.414). ConclusionIL-27 may play an important role in the pathological process in AChR-MG patients, and the frequencies of IL-27-producing (CD3+IL-27+) T cells may be a potential biomarker for predicting the severity of AChR-MG.

Serum IL-21 levels predict HBeAg decline during rescue therapy in patients with partial response to nucleos(t)ide analogues.

To investigate whether IL-21 levels predict treatment outcomes of salvage therapy among patients with suboptimal response (SOR) to nucleos(t)ide analogues (NAs), serum IL-21 levels were measured in a prospective cohort of hepatitis B e antigen (HBeAg)-positive patients with SOR to antiviral therapy. The patients switched therapy to entecavir (ETV) with or without adefovir (ADV) for 104 weeks. IL-21 levels at treatment week 12 in patients who achieved HBeAg loss with undetectable levels of hepatitis B virus (HBV)-DNA at week 104 were the primary endpoint and the results were compared with those of corresponding patients without such an endpoint. Furthermore, IL-21 levels at treatment week 12 in patients who achieved an HBeAg-level decline at week 104 were assessed as the secondary endpoint. Among 24 enrolled patients with SOR to ADV (n=21), telbivudine (n=2) or ETV (n=1), the median (10-90th percentile) levels of HBeAg, HBV-DNA and ALT at baseline were 2.7 (0.2-3.1) log10 S/CO, 5.2 (3.5-7.5) log10 IU/ml and 0.9 (0.5-3.1) upper limit of normal, respectively. Comparison of the patients with and without HBeAg loss at week 104 indicated that their mean IL-21 levels did not significantly differ at week 12 (63.0±14.4 vs. 55.9±10.5 pg/ml; P=0.26). In the secondary endpoint analyses of patients with and without HBeAg level decline, the elevated levels of IL-21 at the first 12 weeks were significantly higher in the decline group (15.6±8.3 vs. 3.1±13.2 pg/ml; P=0.03). Following adjustment for confounding factors, the elevated levels of IL-21 from baseline to week 12 independently predicted an HBeAg level decline at week 104 (odds ratio=1.137, R2=0.23; P=0.047). In conclusion, the serum IL-21 levels at the first 12 weeks during the salvage therapy independently predicted HBeAg level decline at treatment week 104 in patients with SOR to NAs (ClinicalTrials.gov identifier: NCT01829685; date of registration, April 2013).

Stable and exacerbation period serum cytokine and periostin levels of the five distinct phenotypes of severe asthma.

The differences in molecular mechanisms during stable period and the changes in the inflammatory responses during exacerbations between distinct severe asthma phenotypes remain unclear. In this study, we aimed to characterize stable and exacerbation period serum cytokine and periostin levels of 5 different pre-defined severe asthma phenotypes with real-life data. Changes in the viral infection-induced exacerbations were also analyzed. Serum levels of 8 cytokines and periostin were measured from the sera obtained from the adult patients with five different severe asthma phenotypes based on the presence/absence of aeroallergen sensitivity, peripheral eosinophilia and chronic rhinosinusitis with nasal polyposis (CRSwNP) during stable and exacerbation periods, and from the matched controls. Serum IL-13, IL-25, TSLP and periostin levels were similar between the patient and the control groups during stable and exacerbation periods. Serum IL-25 and TSLP levels, and peripheral eosinophil count and periostin level showed a strong correlation. Stable period periostin levels were significantly higher in eosinophilic patients and eosinophilic patients without long-term systemic steroid therapy had higher IL-13 levels. Compared to stable period, exacerbation period serum periostin levels found significantly lower [5853 (2309-8427) pg/mL vs. 4479 (2766-6495) pg/mL; p=0.05] and periostin levels were much more lower in viral infection-induced exacerbations [2913 (893-4770) pg/mL vs. 7094 (4782-9596) pg/mL; p=0.022]. Our study showed that serum periostin levels were decreased in viral infection-induced exacerbations and increased in the presence of eosinophilia independent from atopy and it can help to differentiate eosinophilia even if the patient is under long-term systemic steroid therapy. Also, serum IL-13 levels may reflect peripheral eosinophilia in patients without long term systemic steroid use.

Interleukin-31 new biomarker of infectious skin diseases

Introduction. The introduction of antiretroviral therapy has significantly improved the long-term prognosis of AIDS patients, but opportunistic infections can still be life-threatening for this population. Among them, a large group constitutes of herpesvirus infections, which are frequent manifest forms of dermatological manifestations of HIV. The researching of IL-31, as a prospective diagnostic predictor of dermatological diseases, has been actively conducted in recent years. This is due to the interest in its biological action, which extends primarily to the skin. Тhe identification of molecular targets underlying inflammatory and infectious dermatoses is promisingly for the development of new, targeted treatments. Objective: to study the role of IL-31 in the immunopathogenesis of herpesvirus infections associated with HIV infection. Research objectives: 1) to compare the levels of IL-31 in the blood serum in patients with herpesvirus skin diseases associated with HIV infection and in healthy subjects; 2) to determine the presence of a relationship between the levels of IL-31 in the blood serum and the clinical stage of the disease. Materials and methods. The study included patients with herpesvirus infection caused by HSV-1, HSV-2, VZV-3, EBV and HHV-8 associated with HIV infection and healthy individuals. Serum IL-31 levels were measured by ELISA using commercial kits (Human IL-31 ELISA Kit, Abcam, Cambridge, MA, USA). Were collected the baseline clinical characteristics, assessment of the activity of the infectious process and the degree of immunosuppression. Results. Our study involved 39 patients with herpesvirus infection associated HIV and 31 patients of the control group. In patients with herpesvirus infection against the background of HIV infection, the average level of IL-31 in the blood serum was significantly higher than that of healthy subjects. Serum IL-31 levels in patients with herpesvirus infection did not differ significantly depending on the severity of the process and the degree of immunosuppression. Conclusion. The levels of IL-31 in the blood serum of patients with herpesvirus infection were differed by statistically significant validity in comparison with similar indicators of healthy individuals, which confirms its role in the pathogenesis of infectious skin diseases.

Association Between Serum IL-6, IL-10, IL-12, and IL-23 Levels and Severity of Liver Cirrhosis.

Background:Liver cirrhosis contributes to high liver-related mortality globally. Systemic inflammation mediated by immune cells contributes to the progression of liver cirrhosis. Growing evidence shows that several pro- and anti-inflammatory cytokines might have an important role in liver cirrhosis.Objective:To evaluate the association between serum IL-6, IL-10, IL-12, and IL-23 levels and severity of liver cirrhosis.Methods:This observational study was carried out at the Department of Internal Medicine, Universitas Sumatera Utara, Indonesia from March 2018 to August 2019. The severity of liver cirrhosis was assessed by using the Child-Pugh score. IL-6, IL-10, IL-12, and IL-23 levels, hepatitis and renal function were measured in all study subjects. Independent t-test and Mann-Whitney tests were conducted to observe differences between groups.Results:A total of 78 liver cirrhosis patients were enrolled, mean age was 50.6±11.4. Median serum IL-6, IL-10, IL-12, and IL-23 levels were 24.5(2.6-46.4)pg/ml, 2.1(0.4-9.3)pg/ml, 3.5(1.4-20.8)pg/ml and 20.3(9.2-218)pg/ml, respectively. A higher IL-6 level was associated with more severe liver cirrhosis (p=0.001) and the presence of hepatic encephalopathy (p=0.018). Higher IL-23 level was found in patients with no hepatic encephalopathy (p=0.049). There was no association between serum cytokines levels and hepatitis viral infection status.Conclusion:IL-6 is associated with the severity of liver cirrhosis.