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Interleukin (IL)-35 is an anti-inflammatory cytokine that regulates autoimmune diseases, including systemic lupus erythematosus (SLE). However, the association between the cytokine and disease may vary by geographical region. This study performed a meta-analysis to quantitatively assess the correlation between the serum IL-35 levels in SLE patients and sub-group analyses were conducted. Four main electronic databases-Scopus, Embase, Science Direct, PubMed-were searched for relevant studies. After a database search, Endnote software was used to find and remove duplicate studies. Random-effects models were used to estimate standard mean differences in serum/plasma IL-35 levels by Hedges' g with 95% confidence intervals (CIs). Publication bias was assessed with funnel plots, and risk of bias was assessed according to the Newcastle-Ottawa Scale (NOS). Sixteen studies met the eligibility criteria and were included in a qualitative review; data from 15 studies were included in the meta-analysis. Total IL-35 levels (pg/mL) did not differ among patients with active SLE and healthy controls (Hedges's g: 0.22, 95% CI - 0.51, 0.95, p = 0.55). Sub-group analysis revealed that IL-35 levels in patients with active SLE were lower than in healthy controls in Chinese studies (Hedges's g: - 3.11, 95% CI - 5.72, - 0.51), but not in non-Chinese studies (Hedges's g: 1.63, 95% CI - 0.31, 3.57). This regional difference was statistically significant (p < 0.01). The analysis comparing patients with inactive SLE and healthy controls showed a similar trend. This study suggests that serum IL-35 levels are lower in patients with SLE in studies from China, but not other regions. However, standardized protocols with large sample sizes are needed to confirm these findings., (© 2024. The Author(s).)

In a previous study, it has been shown that the population of Th17 lymphocytes was increased in patients with FMF. IL-21 and IL-23 play significant roles in the production and differentiation of Th17 cells. In this study, we aimed to evaluate serum levels of IL-21 and IL-23 in FMF patients both at diagnosis and after treatment, and to compare these levels with those of healthy controls. Twenty-seven newly diagnosed patients with FMF in attack-free periods and twenty-seven healthy volunteers enrolled in the study. The groups were comparable with respect to age and gender. IL-21 and IL-23 levels in serum samples from patients at the time of diagnosis, in remission after treatment, and from the control groups were analysed using the ELISA method. There was no significant difference between the cytokine levels of the patient group at the time of diagnosis and the cytokine levels of the control group (for IL-21, p: 0.28 and for IL-23, p: 0.56). Similarly, there was no significant difference between the patients' cytokine levels at the time of diagnosis and after treatment (for IL-21, p: 0.99 and for IL-23, p: 0.08). Interleukin levels at the time of diagnosis did not differ among patient groups based on the presence of clinical findings or the M694V genotype. Our results suggest that IL-21 and IL-23 do not play a role in the pathogenesis of the disease. However, while interpreting these findings, it should be considered that patients with active episodes were excluded and cytokine levels were not measured in tissue samples., (© 2024. The Author(s).)

Type III interferons (IFNs) play an important role in respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to determine whether the expression of serum type III IFNs predicted disease severity among patients with the coronavirus disease (COVID-19). A retrospective cohort study was conducted of patients admitted to a single hospital between March 21, 2020, and March 31, 2021. Patients were divided into mild to moderate I (MM) and moderate II to severe (MS) groups based on the COVID-19 severity classification developed by the Japanese Ministry of Health, Labor and Welfare. A total of 257 patients were included in the analysis. Human interleukin-28A (IL-28A/IFN-λ2) expression was significantly lower, and interleukin (IL)-6 expression was significantly higher in the MS group than in the MM group (both p < 0.001). In addition, IL-28A/IFN-λ2 was statistically significantly inversely correlated with the time from disease onset to negative SARS-CoV-2 PCR results (p = 0.049). Multivariable logistic regression analysis showed that IL-28A/IFN-λ2 was an independent predictor of disease severity (p = 0.021). The low expression of IL-28A/IFN-λ2 may serve as a serum biomarker that predicts the severity of COVID-19, possibly through the mechanism of delayed viral elimination., (© 2022. The Author(s).)

Takotsubo syndrome (TTS) is an acute heart failure syndrome with significant rates of in and out-of-hospital mayor cardiac adverse events (MACE). To evaluate the possible role of neoplastic biomarkers [CA-15.3, CA-19.9 and Carcinoembryonic Antigen (CEA)] as prognostic marker at short- and long-term follow-up in subjects with TTS. Ninety consecutive subjects with TTS were enrolled and followed for a median of 3 years. Circulating levels of CA-15.3, CA-19.9 and CEA were evaluated at admission, after 72 h and at discharge. Incidence of MACE during hospitalization and follow-up were recorded. Forty-three (46%) patients experienced MACE during hospitalization. These patients had increased admission levels of CEA (4.3 ± 6.2 vs. 2.2 ± 1.5 ng/mL, p = 0.03). CEA levels were higher in subjects with in-hospital MACE. At long term follow-up, CEA and CA-19.9 levels were associated with increased risk of death (log rank p < 0.01, HR = 5.3, 95% CI 1.9-14.8, HR = 7.8 95% CI 2.4-25.1, respectively, p < 0.01). At multivariable analysis levels higher than median of CEA, CA-19.9 or both were independent predictors of death at long term (Log-Rank p < 0.01). Having both CEA and CA-19.9 levels above median (> 2 ng/mL, > 8 UI/mL respectively) was associated with an increased risk of mortality of 11.8 (95% CI 2.6-52.5, p = 0.001) at follow up. Increased CEA and CA-19.9 serum levels are associated with higher risk of death at long-term follow up in patients with TTS. CEA serum levels are correlated with in-hospital MACE., (© 2021. The Author(s).)

No clear consensus on the need to perform an intracorporeal anastomosis (IA) after laparoscopic right colectomy is currently available. One of the potential benefits of intracorporeal anastomosis may be a reduction in surgical stress. Herein, we evaluated the surgical stress response and the metabolic response in patients who underwent right colonic resection for colon cancer. Fifty-nine patients who underwent laparoscopic resection for right colon cancer were randomized to receive an intracorporeal or an extracorporeal anastomosis (EA). Data including demographics (age, sex, BMI and ASA score), pathological (AJCC tumour stage and tumour localization) and surgical results were recorded. Moreover, to determine the levels of the inflammatory response, mediators, such as C-reactive protein (CRP), tumour necrosis factor (TNF), interleukin 1β (IL-1β), IL-6, IL-10, and IL-13, were evaluated. Similarly, cortisol and insulin levels were evaluated as hormonal responses to surgical stress. We found that the proinflammatory mediator IL-6, CRP, TNF and IL-1β levels, were significantly reduced in IA compared to EA. Concurrently, an improved profile of the anti-inflammatory cytokines IL-10 and IL-13 was observed in the IA group. Relative to the hormone response to surgical stress, cortisol was increased in patients who underwent EA, while insulin was reduced in the EA group. Based on these results, surgical stress and metabolic response to IA justify advocating the adoption of a totally laparoscopic approach when performing a right colectomy for cancer.This trial is registered on ClinicalTrials.gov (ID: NCT03422588).

Abatacept, an inhibitor of CD28 mediated T-cell activation, has been shown to be effective in controlling inflammation during rheumatoid arthritis (RA). However, its effects on immune regulatory B and T cells (Bregs and Tregs) has not been fully explored. Thirty-one RA patients treated with abatacept for ≥ 6 months along with 31 RA patients treated with other modalities as well as 30 healthy controls were recruited. Of these 62 RA patient, 49 (79%) were females with a mean age of 54 ± 12 years and disease duration of 10 ± 6 years. The blood levels of Tregs and Bregs and their production of immunosuppressive cytokines, were determined using FACS analysis and Luminex Multiplex assay. Treatment with abatacept significantly enhanced the blood level of IL-35 + IL-10 + Bregs (P = 0.0007). Their levels were higher in the blood of remitted patients (DAS28-CRP < 2.6) compared to the unremitted ones (P = 0.0173), 6 months following abatacept treatment initiation. Moreover, abatacept treatment significantly enhanced the blood levels of LAG3 + conventional and unconventional Tregs of RA patients. This increase in the blood levels of Bregs and Tregs was accompanied with an elevated serum level of IL-35 and IFN-β in abatacept-treated patients. Therefore, Abatacept efficiency to achieve remittance in RA could be attributed, in part, to its ability to enhance immune regulatory cells, especially IL-135 + IL-10 + Bregs.

Spondyloarthritis (SpA) is characterized by inflammation and new bone formation. The exact pathophysiology underlying these processes remains elusive. We propose that the extensive neoangiogenesis in SpA could play a role both in sustaining/enhancing inflammation and in new bone formation. While ample data is available on effects of anti-TNF on angiogenesis, effects of IL-17A blockade on serum markers are largely unknown. We aimed to assess the impact of secukinumab (anti-IL-17A) on synovial neoangiogenesis in peripheral SpA, and how this related to changes in inflammatory and tissue remodeling biomarkers. Serum samples from 20 active peripheral SpA patients included in a 12 week open-label trial with secukinumab were analyzed for several markers of angiogenesis and tissue remodeling. Synovial biopsies taken before and after treatment were stained for vascular markers. Serum levels of MMP-3, osteopontin, IL-6 (all P < 0.001), IL-31, S100A8, S100A9, Vascular Endothelial Growth Factor A (VEGF-A), IL-33, TNF-α (all P < 0.05) decreased significantly upon anti-IL17A treatment. Secukinumab treatment resulted in a decrease in the number of synovial high endothelial venules and lymphoid aggregate score. These results indicate that anti-IL-17A not only diminishes inflammation, but also impacts angiogenesis and tissue remodeling/new bone formation. This may have important implications for disease progression and/or structural damage.

Immune regulation status may indicate immunological remission in rheumatoid arthritis (RA). This cross-sectional study aimed to determine the Regulatory T cell (Treg) properties, together with 14 plasma cytokines levels between active RA and clinical remission patients. Peripheral blood (PB) Foxp3+ Treg was collected from RA patients for determination of Treg inhibitory activity using a co-culture system. Other PB T cell types and plasma cytokines were determined by flow-cytometry. The Treg results were analyzed according to the disease activity score-28 (DAS28). Then sensitivity and specificity were calculated for the indication of the remission status. The number and inhibitory activity of Treg are higher in the clinical remission as compared to the active RA (p value < 0.0001). Also, Treg: CD4+CD25+CD127+ cell ratio demonstrates the similar result (p value < 0.05). Treg inhibitory activity is inversely correlated with the DAS28. Specificity and positive likelihood ratio of inhibitory activity for indicating remission status are 92.31% (95% CI 63.97-99.81) and 11.14 (95% CI 1.67-74.14), respectively. Treg inhibitory activity is a promising prognostic marker and probably represents the immunological remission status in RA.

Endoscopy is a central tool for diagnosing and evaluating paediatric inflammatory bowel diseases (PIBD), but is too invasive to be frequently repeated in young children. Furthermore, it is challenging to distinguish Crohn's disease (CD) from ulcerative colitis (UC) endoscopically. This study aimed to determine biomarkers useful for the diagnosis of PIBD. Cytokines, chemokines, and growth factors were quantified in the sera of 15 patients with CD or UC, at disease onset prior to treatment, and 26 age-matched controls. Correlation of cytokine levels with the paediatric CD activity index (PCDAI) and the paediatric UC activity index (PUCAI) was analysed. Interleukin (IL)-6, IL-13, IL-7, and vascular endothelial growth factor were higher in the CD group than in the UC group. The receiver operating characteristic curve analysis showed that IL-7 was a putative biomarker for distinguishing CD from UC (area under the curve: 0.94). Granulocyte-macrophage colony-stimulating factor was associated with PCDAI, and an IL-1 receptor antagonist, IL-6, and macrophage inflammatory protein-1β were associated with PUCAI. These findings indicate significant differences in cytokine signatures among patients with new-onset PIBD, which may improve accuracy in diagnosing PIBD.

This study was to investigate the association between serum interleukin 32 (IL-32) concentration and clinical parameters in patients with stable chronic obstructive pulmonary disease (COPD). One hundred and sixteen patients with stable COPD and 70 healthy subjects were included in the study. The serum concentration of IL-32 was detected by enzyme-linked immunosorbent assay. The correlation between serum IL-32 and clinical parameters of patients with COPD was analyzed by T-test, one-way analysis of variance, multiple linear regression and receiver operating characteristic curve. The serum concentration of IL-32 in patients with stable COPD was higher than that in healthy control group (p < 0.001) and increased serum IL-32 was positively correlated with GOLD grading (p = 0.026), mMRC score (p = 0.004) and clinical medical history (p = 0.005), but negatively related to FEV1/FVC (p = 0.001) and FEV1% predicted (p = 0.001). Patient's COPD grading (p = 0.001), clinical medical history (p < 0.001) and FEV1/FVC (p = 0.001) exerted a significant impact on serum IL-32. The sensitivity and specificity of serum IL-32 for discerning COPD patients from healthy individuals were 85.34% and 64.29%, and the area under the curve was 0.808 (p < 0.001). Increased IL-32 is involved in the chronic disease progression of COPD, suggesting that IL-32 may be a molecular biomarker that reflects the severity of COPD and contributes to the disease diagnosis.

The main factors involved in the pathogenesis of atopic dermatitis (AD) are skin barrier abnormality, allergy/immunology, and pruritus. Considering how oxidative stress influences these factors, antioxidant agents may be effective candidates in the treatment of AD. To evaluate the effect of Caffeoyl-Pro-His amide (CA-PH), an antioxidant agent, on 2,4-dinitrochlorobenzene (DNCB)-induced AD-like phenotypes in BALB/c mice. Topical sensitization and challenge by DNCB were performed on the dorsal skin of BALB/c mice to induce AD-like cutaneous lesions, phenotypes, and immunologic response. CA-PH was applied topically for 2 weeks to assess its effects on DNCB-induced AD-like phenotypes. As a result, CA-PH relieved DNCB-induced AD-like phenotypes quantified by dermatitis severity score, scratching duration, and trans-epidermal water loss. Histopathological analysis showed that CA-PH decreased epidermal thickening, the number of mast cells, and eosinophil infiltration in dermis. Immunohistochemical staining revealed that CA-PH recovered skin barrier-related proteins: filaggrin, involucrin, and loricrin. As for the immunologic aspects, CA-PH treatment lowered mRNA or protein levels of interleukin (IL)-4, IL-6, IL-17a, IL-1b, IL-31, and IL-33 levels and thymic stromal lymphopoietin (TSLP) levels in cutaneous tissue, reducing the DNCB-induced serum IgE level elevation. In conclusion, topical CA-PH may be a therapeutic option for the treatment of AD.

This study aimed to investigate whether interleukin-34 (IL-34) mRNA expression is aberrant and modulated by tumor necrosis factor-alpha (TNF-α) in knee osteoarthritis (OA) fibroblast-like synoviocytes (FLS) and determine associations of IL-34 mRNA and protein in the systemic and local joint environments with severity of knee OA synovitis. Transcriptional and translational IL-34 levels in FLS, synovium, synovial fluid, and plasma of knee OA were determined using real-time polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay. Relative mRNA expressions of NF-κB signaling molecules were further measured. In knee OA FLS stimulated with TNF-α, IL-34 mRNA expression was significantly up-regulated in a time-dependent manner. In knee OA synovium with severe synovitis, increased IL-34 mRNA expression was directly associated with IL-6, IκB, NF-κB, and MMP-13, in addition to knee OA FLS. Immunostaining score of IL-34 was considerably greater in knee OA synovium with severe synovitis than that in those with mild and no synovitis. Increments in joint fluid and plasma IL-34 levels in knee OA patients with severe synovitis were closely related to its mRNA and protein expressions in knee OA synovium. Transcriptional and translational expressions of IL-34 were positively correlated with synovitis severity. Collectively, IL-34 overexpression would reflect synovitis severity in knee OA.

Recent research has identified a population of PD-1 hi CXCR5 - 'peripheral helper' T (Tph) cells that simulate plasma cell differentiation by interactions between IL-21 and SLAMF5. However, the alteration of circulating Tph and CD138 + B in IgA nephropathy (IgAN) remains poorly understood. Flow cytometry analysis was used to measure the frequency of circulating PD-1 hi CXCR5 - T cells and CD138 + B cells in 37 patients with IgAN and 23 healthy controls (HCs). Estimated glomerular filtration rate (eGFR), 24 h urinary protein and serum cytokine concentrations were measured. The percentage of different subsets of circulating PD-1 hi CXCR5 - T cells and CD138 + B cells were significantly higher in patients with IgAN compared to HCs. Pretreatment, the percentage of different subsets of circulating PD-1 hi CXCR5 - T cells and CD138 + B cells were negatively correlated with eGFR, the percentage of circulating CD138 + B cells was positively correlated with 24-h urinary protein concentration, and the percentage of circulating PD-1 hi CXCR5 - , CD28 + and ICOS + T cells. Posttreatment, the percentage of different subsets of circulating PD-1 hi CXCR5 - T cells and CD138 + B cells and serum IL-21 concentration were significantly reduced. Different subsets of circulating PD-1 hi CXCR5 - T cells contribute to the progression and pathogenesis of IgAN by regulating the differentiation of CD138 + B cells through a combination of surface molecules.

Interleukin (IL)-34 plays a critical role in cell proliferation, differentiation, apoptosis, angiogenesis, inflammation and immunoregulation. Numerous diseases can be attributed to the dysregulation of IL-34 signaling. This study was performed to investigate the function of IL-34 in the pathogenesis of endometriosis. Firstly, by enzyme linked immunoabsorbent assay, we found that IL-34, VEGF, MMP-2 and MMP-9 were increased in the sera of patients with endometriosis. Secondly, exposure to IL-34 promoted the proliferation, migration and invasion of eutopic endometrial stromal cells (ESCs). Additionally, stimulation with IL-34 up-regulated colony-stimulating factor 1 receptor (CSF1R), p-JAK3, p-STAT6, VEGF, MMP-2 and MMP-9 in these eutopic ESCs. Treatment with AS1517499, an inhibitor of STAT6, remarkably abrogated the alterations induced by IL-34. A Chromatin immunoprecipitation (ChIP) assay demonstrated binding of STAT6 to the IL-34 promoter, further implicating STAT6 in IL-34 signaling. Notably, reverse results were obtained in ectopic ESCs with the application of an IL-34 neutralizing antibody. In vivo, AS1517499 suppressed the maintenance of endometriosis lesions in rats. In summary, autocrine production of IL-34, mediated by STAT6, promoted the development of endometriosis in vitro and in vivo through the CSF1R/JAK3/STAT6 pathway. Our research reveals the function of IL-34 in endometriosis, which may provide insight into novel therapeutic strategies for endometriosis.

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that is associated with the destruction of immune tolerance and activation of B cells. Interleukin (IL)-35 and IL-35-producing (IL-35 + ) regulatory B cells (Bregs) have been demonstrated to possess immunosuppressive functions, but their roles in the initiation and early development of SLE have not been explored. Here, we measured and compared the frequencies of blood regulatory B cell subsets and the concentrations of plasma IL-35, IL-10, IL-17A, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in 47 Chinese patients with newly diagnosed SLE and 20 matched healthy controls (HCs). The SLE patients had decreased percentages of IL-35 + B cells and IL-10 + B cells among the total blood B cells as well as decreased concentrations of plasma IL-35. In addition, higher levels of plasma IL-10, IFN-γ, TNF-α, and IL-17 along with higher frequencies of circulating plasma and memory B cells were observed in the SLE patients. The percentage of IL-35 + Bregs and the serum IL-35 level were inversely correlated with the SLE disease activity index and the erythrocyte sedimentation rate (ESR) levels. Our results indicate that IL-35 + Bregs and IL-35 may play protective roles in SLE initiation and progression.

Bicuspid aortic valve (BAV) disease is recognized to be a syndrome with a complex and multifaceted pathophysiology. Its progression is modulated by diverse evolutionary conserved pathways, such as Notch-1 pathway. Emerging evidence is also highlighting the key role of TLR4 signaling pathway in the aortic valve pathologies and their related complications, such as sporadic ascending aorta aneurysms (AAA). Consistent with these observations, we aimed to evaluate the role of TLR4 pathway in both BAV disease and its common complication, such as AAA. To this aim, 70 subjects with BAV (M/F 50/20; mean age: 58.8 ± 14.8 years) and 70 subjects with tricuspid aortic valve (TAV) (M/F 35/35; mean age: 69.1 ± 12.8 years), with and without AAA were enrolled. Plasma assessment, tissue and gene expression evaluations were performed. Consistent with data obtained in the previous study on immune clonotypic T and B altered responses, we found reduced levels of systemic TNF-α, IL-1, IL-6, IL-17 cytokines in BAV cases, either in the presence or absence of AAA, than TAV cases (p < 0.0001 by ANOVA test). Interestingly, we also detected reduced levels of s-TLR4 in BAV cases with or without AAA in comparison to the two groups of TAV subjects (p < 0.0001 by ANOVA test). These results may suggest a deregulation in the activity or in the expression of TLR4 signaling pathway in all BAV cases. Portrait of these data is, indeed, the significantly decreased gene expression of inflammatory cytokines and TLR4, in both normal and aneurysmatic tissue samples, from BAV with AAA than TAV with AAA. In conclusion, our study demonstrates that subjects with BAV display a significant deregulation of TLR4 signaling pathway paralleled by a deregulation of Notch-1 pathway, as previously showed. This data suggests that the crosstalk between the Notch-1 and TLR4 signaling pathways may play a crucial role in both physiological embryological development, and homeostasis and functionality of aortic valve in adult life.

Because development of reliable biomarkers in psoriasis and atopic dermatitis has lagged behind therapeutic progress, we created a blood-based test to fill the void in objective methods available for dermatological assessments. Our novel interleukin-19 (IL-19) immunoassay was initially tested to determine concentrations of IL-19 serum levels, then correlated with the psoriasis activity and severity index (PASI) in psoriasis, and the eczema area and severity index (EASI) in atopic dermatitis. Not only was IL-19 increased in psoriasis and correlated to PASI, but ixekizumab administration led to rapid, sustained IL-19 decreases to normal levels, with decreases at 2-weeks correlating with PASI improvement at 16-weeks. IL-19 increased upon ixekizumab withdraw, prior to relapse, and decreased following re-treatment. In baricitinib- and etanercept-treated psoriasis patients, IL-19 decreases also correlated with improvement. Many patients with limited skin disease, including genital psoriasis and psoriatic arthritis patients, also had increased IL-19, which was reduced to normal levels upon ixekizumab treatment, correlating with PASI improvement. We also measured IL-19 in baricitinib-treated atopic dermatitis patients. In atopic dermatitis, IL-19 was significantly elevated, correlated with EASI scores, and decreased with skin improvement. Therefore, measurement of serum IL-19 provides clinicians with an objective disease-activity assessment tool for psoriasis and atopic dermatitis patients.

We have developed a transgenic mouse model of Type 1 Diabetes (T1D) in which human GAD65 is expressed in pancreatic β-cells, and human MHC-II is expressed on antigen presenting cells. Induced GAD65 antigen presentation activates T-cells, which initiates the downstream events leading to diabetes. In our humanized mice, we have shown downregulation of eukaryotic translation initiation factor 5 A (elF5A), expressed only in actively dividing mammalian cells. In-vivo inhibition of elF5A hypusination by deoxyhypusine synthase (DHS) inhibitor "GC7" was studied; DHS inhibitor alters the pathophysiology in our mouse model by catalyzing the crucial hypusination and the rate-limiting step of elF5A activation. In our mouse model, we have shown that inhibition of eIF5A resets the pro-inflammatory bias in the pancreatic microenvironment. There was: (a) reduction of Th1/Th17 response, (b) an increase in Treg numbers, (c) debase in IL17 and IL21 cytokines levels in serum, (d) lowering of anti-GAD65 antibodies, and (e) ablation of the ER stress that improved functionality of the β-cells, but minimal effect on the cytotoxic CD8 T-cell (CTL) mediated response. Conclusively, immune modulation, in the case of T1D, may help to manipulate inflammatory responses, decreasing disease severity, and may help manage T1D in early stages of disease. Our study also demonstrates that without manipulating the CTLs mediated response extensively, it is difficult to treat T1D.

Obesity has been identified as a risk factor for adverse outcomes of various diseases. However, information regarding the difference between the response of obese and normal subjects to pulmonary inflammation is limited. Mice were fed with the control or high-fat diet to establish the lean and diet-induced obese (DIO) mice. Escherichia coli was intranasally instilled to reproduce non-fatal acute pneumonia model. After infection, serum samples and lung tissues were obtained at 0, 12, 24, and 72 h. DIO mice exhibited increased serum triglyceride (TG) and total cholesterol (TC) contents as well as pulmonary resistin, IL-6, and leptin levels compared with lean mice. E. coli infection caused an acute suppurative inflammation in the lung with increased lung index and serum TG and TC contents; elevated pulmonary tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, and leptin levels; and oxidative stress in mice. Interestingly, almost all the above-mentioned parameters peaked at 12 h after infection in the lean-E. coli group but after 12 h in the DIO-E. coli group. These results indicated that the DIO mice presented a delayed inflammatory response and oxidative stress in non-fatal acute pneumonia induced by E. coli infection.

In spondyloarthritis, little is known about the relation between circulating cytokines and patient phenotype. We have quantified serum levels of T helper type 1 cell (Th1), Th2 and Th17 cytokines in patients with recent-onset axial spondyloarthritis (AxSpA) from the DESIR cohort, a prospective, multicenter French cohort consisting of 708 patients with recent-onset inflammatory back pain (duration >3 months but <3 years) suggestive of AxSpA. Serum levels of Th1, Th2, and Th17 cytokines were assessed at baseline in patients from the DESIR cohort fulfilling the ASAS criteria (ASAS+) and were compared with age- and sex-matched healthy controls. At baseline, ASAS+ patients (n = 443) and healthy controls (n = 79) did not differ in levels of most of the Th1, Th2 and Th17 cytokines except for IL-31, and sCD40L, which were significantly higher for ASAS+ patients than controls (p < 0.001 and p = 0.012, respectively). On multivariable analysis of ASAS+ patients, IL-31 level was associated with sCD40L level (p < 0.0001), modified Stoke AS Spine Score (mSASSS) < 1 (p = 0.035). The multivariable analyses showed that IL-31 was an independent factor associated with mSASSS < 1 (p = 0.001) and low bone mineral density (p = 0.01). Increased level of IL-31 might protect against structural damage but is also related to low BMD.

Atopic dermatitis (AD) is a chronic inflammatory immune-mediated skin disease characterized by skin colonization by Staphylococcus aureus. Interleukin (IL)-22, in cooperation with IL-17, triggers antimicrobial peptide elaboration and enhances certain immunological responses. In AD, IL-22 is related to epidermal hyperplasia, keratinocyte apoptosis, and inhibition of antimicrobial peptide (AMP) production. We aimed to evaluate the impact of staphylococcal enterotoxins on the Tc22/Th22 induction in the peripheral blood of AD patients and on CD4 +/ CD8 + T cells expressing IL-22 in AD skin. Our study showed inhibition of the staphylococcal enterotoxins A and B (SEA and SEB) response by Th22 (CD4 + IL-22 + IL-17A - IFN-γ - ) cells in AD patients. In contrast, Tc22 (CD8 + IL-22 + IL-17A - IFN-γ - ) cells were less susceptible to the inhibitory effects of staphylococcal enterotoxins and exhibited an enhanced response to the bacterial stimuli. In AD skin, we detected increased IL-22 transcript expression and T lymphocytes expressing IL-22. Together, our results provide two major findings in response to staphylococcal enterotoxins in adults with AD: dysfunctional CD4 + IL-22 secreting T cells and increased Tc22 cells. Our hypothesis reinforces the relevance of CD8 T cells modulated by staphylococcal enterotoxins as a potential source of IL-22 in adults with AD, which is relevant for the maintenance of immunological imbalance.

We measured the interleukin-34 (IL-34) level in sera from patients with systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE) using an enzyme-linked immunosorbent assay (ELISA). Blood tests, including assays to determine C-reactive protein (CRP), complement (C) 3, C4, immunoglobulin (Ig) A, IgG, IgM, anti-double-stranded DNA antibody (Anti-dsDNA Ab) and hemoglobin (Hb) levels and white blood cell (WBC) and platelet (PLT) counts, were performed using standard methods. Lupus nephritis (LN) was diagnosed according to the American College of Rheumatology (ACR) renal criteria. The SLE disease activity was scored using the SLE Disease Activity Index (SLEDAI). Among the 110 SLE cases, IL-34 could be detected in 79 cases (71.8%). IL-34 was barely detected in the control group. The serum level of IL-34 was significantly higher in the SLE group. No change was observed in the serum IL-34 concentration in the SLE patients regardless of LN status. Correlations were observed between the serum IL-34 level and the disease activity parameters. The SLE patients with detectable IL-34 levels had higher SLEDAI and IgG concentrations and lower C3 and Hb levels than patients with undetectable IL-34 levels. Therefore, IL-34 could be a potential disease activity marker for SLE.

Saliva collection is considered a non-invasive method to detect inflammatory markers in response to emotional states within natural social contexts. Numerous studies have prompted an important role of cytokines in modulating distinct aspects of social and emotional behavior. The aim of this study was to investigate the reliability of plasma and saliva as investigative tools for measure some inflammatory marker levels (CRP, IL-1β, IL-18, and IL-6). At the same time, the relationships between these markers and emotional states in response to a socio-cognitive stress (Academic Exam, AE), were considered. It was demonstrated that the plasma and saliva concentrations of all immune-mediators analyzed were significantly related across the socio-cognitive stress. In addition, when there was a close correlation to AE, the anger state, the IL-1β, the IL-18 salivary and plasmatic concentrations were significantly higher, while they decreased during the AE. On the other hand, the anxiety state and the IL-6 levels significantly increased throughout the AE. The IL-1β and IL-6 were positively associated to the anger and the anxiety state, respectively. In conclusion, our data highlight that different immune markers are similarly detectable in plasma and saliva during socio-cognitive stress. Also, they could be related to different emotional responses.

IL-23 and IL-27 are believed to be involved in the pathogenesis of Guillain-Barré syndrome (GBS). However, changes in these cytokines during the dynamic pathological and recovery processes of GBS are not well described. In the present study, plasma was collected from 83 patients with various stages of GBS, 70 patients with central nervous system demyelinating diseases,70 patients with other neurological diseases (OND) and 70 age- and sex-matched healthy volunteers. Serum levels of IL-23, IL-27, and Campylobacter jejuni (CJ) IgM were assessed using enzyme linked immunosorbent assay (ELISA). We found that serum IL-23 levels of patients during the acute phase of GBS were significantly higher followed by a decreasing trend during the recovery phase of the disease. Serum IL-27 levels significantly increased during the acute phase of GBS, and gradually increased during the recovery phase. Interestingly, both the severity and subtype of GBS were closely associated with the two cytokines. IL-23 levels were positively correlated with IL-27 levels, prognosis, and other clinical parameters. Our findings confirm that IL-23 may show pro-inflammatory effects, especially at the early stage of GBS. IL-27 appears to have a dual role in GBS, with initial pro-inflammatory effects, followed by anti-inflammatory properties during recovery.

Chronic spontaneous urticaria (CSU) is considered in a subset of patients to be an autoimmune disorder. Interleukin(IL)-17, IL-31, and IL-33 are involved in some immune response. The aim of this study was to quantify plasma IL-17, IL-31, and IL-33 levels in CSU patients and to examine their relationships with disease severity. Plasma IL-17, IL-31, and IL-33 concentration were measured in 51 CSU patients and 20 healthy subjects (HCs). Plasma IL-17 (P < 0.001), IL-31 (P < 0.001), and IL-33 (P < 0.001) concentrations were significantly higher in CSU patients when compared with those of HCs. Concerning UAS7, severe group of CSU patients had significantly higher IL-17 levels than the moderate and mild groups (P = 0.028 and 0.007, respectively), and significantly higher IL-33 concentrations than the mild group (P = 0.026). Regarding only pruritus, severe group of patients had significantly higher IL-31 levels than the mild group (P = 0.003). The IL-33 levels in the total IgE positive group were significantly higher than that of negative group (P = 0.010). Our results showed higher plasma levels of IL-17, IL-31, and IL-33 among CSU patients which may highlight a functional role of these cytokines in the pathogenesis of CSU.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a variety of pathological features. Our study investigated the potential role of CCR6 + T cells in organ impairment of SLE patients. We analyzed CCR6 +/- T cell subset populations and compared the concentrations of IL-22, IFN-γ, TNF-α, and IL-17A cytokines in 67 patients with newly diagnosed SLE and 26 healthy controls. We found that SLE patients had elevated percentages of CCR6 + T, CCR6 + Th22, Th17, Th17.1, and CCR6 - Th2 cell subsets, along with increased concentrations of IL-22, IFN-γ, TNF-α, and IL-17 cytokines. Higher levels of CCR6 + T and CCR6 + Th22 cells, along with plasma IL-22 were observed in SLE patients with sole skin and/or renal impairment. The percentage of Th22 cells also correlated with Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI) and IgG levels, and inversely correlated with C3 levels in SLE patients with sole skin impairment. SLE patients with sole renal impairment showed a correlation between the percentage of Th22 cells and ESR levels. Our data indicated that CCR6 + Th22 cells may contribute to the pathogenesis of new onset SLE patients with skin or renal impairment, and CCR6 may, thus, be a possible therapeutic target for SLE treatment.

SERS-active nanostructures incorporated into a microfluidic device have been developed for rapid and multiplex monitoring of selected Type 1 cytokine (interleukins: IL-6, IL-8, IL-18) levels in blood plasma. Multiple analyses have been performed by using nanoparticles, each coated with different Raman reporter molecules: 5,5'-dithio-bis(2-nitro-benzoic acid) (DTNB), fuchsin (FC), and p-mercatpobenzoic acid (p-MBA) and with specific antibodies. The multivariate statistical method, principal component analysis (PCA), was applied for segregation of three different antigen-antibody complexes encoded by three Raman reporters (FC, p-MBA, and DTNB) during simultaneous multiplexed detection approach. To the best of our knowledge, we have also presented, for the first time, a possibility for multiplexed quantification of three interleukins: IL-6, IL-8, and IL-18 in blood plasma samples using SERS technique. Our method improves the detection limit in comparison to standard ELISA methods. The low detection limits were estimated to be 2.3 pg·ml -1 , 6.5 pg·ml -1 , and 4.2 pg·ml -1 in a parallel approach, and 3.8 pg·ml -1 , 7.5 pg·ml -1 , and 5.2 pg·ml -1 in a simultaneous multiplexed method for IL-6, IL-8, and IL-18, respectively. This demonstrated the sensitivity and reproducibility desirable for analytical examinations.

This study is to investigate the frequencies of T-helper (Th)22, Th17 and Th1 cells and the levels of related cytokines in subchondral bone marrow in patients with rheumatoid arthritis (RA). Bone marrow and peripheral blood samples were collected from RA, osteoarthritis (OA) patients and healthy controls. The frequencies of Th22, Th17, and Th1 cells were examined by flow cytometry. Levels of interleukin (IL)-22, IL-17 and IFN-γ were examined by ELISA. Disease Activity Score in 28 joints (DAS28) of RA patients were analyzed. Bone marrow Th22, Th17 and Th1 cells in RA patients were markedly increased comparing to OA or healthy controls. Each T cell subset in bone marrow was elevated comparing with that in the peripheral blood in RA patients. Consistently, plasma levels of IL-22 and IL-17 were elevated in RA patients, and the elevation was more notable in the bone marrow than in the peripheral blood. Additionally, the percentages of Th22, Th17 and Th1 cells as well as the levels of IL-22 and IL-17 in bone marrow were positively correlated with DAS28. These results suggest that local pro-inflammatory Th cells are elevated in bone marrow, which may play an important role in situ in RA and contribute to the pathogenesis of in RA.

T cells are key players in immune-mediated rheumatoid arthritis (RA). We previously reported that interleukin (IL)-22 + CD4 + T helper (IL-22 + Th) cells and IL-22 critically control the pathogenesis of RA. Here we monitored circulating levels of different IL-22 + Th cell subsets and measured plasma levels of IL-22, IL-17, and interferon (IFN)-γ in 60 patients with active RA following 12-week combination methotrexate (MTX) and leflunomide (LEF) therapy (MTX+LEF) and 20 healthy individuals. We found the frequencies of circulating IFN-γ - IL-17 - IL-22 + (Th22), IFN-γ - IL-17 + (total Th17), IFN-γ + IL-17 - IL-22 + (IL-22 + Th1) cells, and IFN-γ - IL-17 + IL-22 + (IL-22 + Th17) cells, as well as the plasma levels of IL-22, IL-17 and IFN-γ to be significantly reduced in RA patients that responded to treatment, but not in non-responders. Reductions in plasma IL-22 level significantly correlated with percentage of circulating Th22 cells and the decrease of plasma IL-22 level correlated with the reduction of DAS28 in responders. Our data suggests that circulating Th22 cells and plasma IL-22 level play a detrimental role in RA. The combination MTX+LEF therapy, by targeting Th22 cells and reducing IL-22 level, relieves the immune defects and ameliorates symptoms of RA. This study provides novel mechanistic understanding of the pathogenesis of RA, which may promote a design of better therapies for RA., Competing Interests: The authors declare that they have no competing financial interests.

Interleukin-32 gamma (IL-32γ) is a recently discovered cytokine that is elevated in inflamed tissues and contributes to pathogenic features of bone in human inflammatory rheumatic diseases. Nevertheless, the role of IL-32γ and its direct involvement in bone metabolism is unclear. We investigated the molecular mechanism of IL-32γ in bone remodeling and the hypothetical correlation between IL-32γ and disease activity in osteoporosis patients. Transgenic (TG) mice overexpressing human IL-32γ showed reduced bone loss with advancing age, increased bone formation, and high osteogenic capacity of osteoblast compared to wild-type (WT) mice through the upregulation of miR-29a, which caused a reduction of Dickkopf-1 (DKK1) expression. IL-32γ TG mice were protected against ovariectomy (OVX)induced osteoporosis compared with WT mice. Decreased plasma IL-32γ levels were associated with bone mineral density (BMD) in human patients linked to increased DKK1 levels. These results indicate that IL-32γ plays a protective role for bone loss, providing clinical evidence of a negative correlation between IL-32γ and DKK1 as bone metabolic markers.

Pro-inflammatory mediators are identified in patients with heart failure (HF), some of which may be used as biomarkers with diagnostic or prognostic value. As an additional ligand of Colony Stimulating Factor-1 Receptor (CSF-1R), interleukin-34 (IL-34) has been identified as a pro-inflammatory cytokine participating in chronic heart failure (CHF). However, the potential impact of IL-34 in CHF complications remains unknown. In order to determine the clinical significance of serum IL-34 in CHF patients, especially those with kidney dysfunction and coronary artery disease (CAD) comorbid conditions, serum IL-34 was measured in 510 consecutive patients with CHF in a cross-sectional study. The present study demonstrated that higher serum IL-34 levels were associated with poorer renal function and more severe anemia in patients with CHF. After adjusting for age, gender, conventional risk factors, and other significant covariates, IL-34 positively correlated with the presence and severity of renal dysfunction (as measured by eGFR and cystatin C) on multivariable linear and logistic regression analysis. IL-34 was also demonstrated to be an independent risk factor for CAD among HF patients. In conclusion, elevated serum IL-34 levels were demonstrated to be independently associated with renal insufficiency and CAD in patients with CHF, regardless of the systolic function.

Occupational exposure to air pollution induces oxidative stress and prolonged exposure increases susceptibility to cardiovascular and respiratory diseases in several working groups. Biofluid of these subjects may reflect perturbed metabolic phenotypes. In this study we carried out a comparative molecular profiling study using parallel biofluids collected from subjects (n = 85) belonging to auto rickshaw drivers (ARD), traffic cops (TC) and office workers (OW). Higher levels of oxidative stress and inflammation markers in serum of ARD subjects were observed as compared to OW and TC. Uni and multivariate analyses of metabolites identified in urine by 1 H NMR revealed 11 deregulated molecules in ARD subjects and involved in phenylalanine, histidine, arginine and proline metabolism. Despite contribution of confounding factors like exposure period, dietary factors including smoking and alcohol status, our results demonstrate existence of exposure specific metabotypes in biofluids of ARD, OW and TC groups. Monitoring serum oxidative stress and inflammation markers and urine metabolites by NMR may be useful to characterize perturbed metabolic phenotypes in populations exposed to urban traffic air pollution.

Chronic sleep fragmentation (SF) commonly occurs in human populations, and although it does not involve circadian shifts or sleep deprivation, it markedly alters feeding behaviors ultimately promoting obesity and insulin resistance. These symptoms are known to be related to the host gut microbiota. Mice were exposed to SF for 4 weeks and then allowed to recover for 2 weeks. Taxonomic profiles of fecal microbiota were obtained prospectively, and conventionalization experiments were performed in germ-free mice. Adipose tissue insulin sensitivity and inflammation, as well as circulating measures of inflammation, were assayed. Effect of fecal water on colonic epithelial permeability was also examined. Chronic SF-induced increased food intake and reversible gut microbiota changes characterized by the preferential growth of highly fermentative members of Lachnospiraceae and Ruminococcaceae and a decrease of Lactobacillaceae families. These lead to systemic and visceral white adipose tissue inflammation in addition to altered insulin sensitivity in mice, most likely via enhanced colonic epithelium barrier disruption. Conventionalization of germ-free mice with SF-derived microbiota confirmed these findings. Thus, SF-induced metabolic alterations may be mediated, in part, by concurrent changes in gut microbiota, thereby opening the way for gut microbiome-targeted therapeutics aimed at reducing the major end-organ morbidities of chronic SF.

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. Activation of macrophages and hepatic stellate cells is a critical step that promotes liver fibrosis. We aimed to explore the feasibility of interleukin-34 (IL-34), a key regulator of macrophages, as a fibrosis marker in patients with NAFLD. We enrolled 197 liver biopsy-proven NAFLD patients. We evaluated the serum levels of IL-34, macrophage-colony stimulating factor (M-CSF), soluble CD163 (sCD163), 40 cytokines/chemokines, hyaluronic acid, type IV collagen 7s, and clinically-approved fibrosis scores. IL-34 increased with the progression of fibrosis and was an independent marker for liver fibrosis. Immunostaining experiments, using resected liver specimens from NAFLD patients, revealed that IL-34 was mainly expressed on liver fibroblasts. IL-34 based fibrosis score (0.0387*IL-34 (pg/ml) + 0.3623*type IV collagen 7s (ng/ml) + 0.0184*age (year)-1.1850) was a practical predictive model of liver fibrosis. Using receiver-operating characteristic analyses, the area under the curve, sensitivity, and specificity of IL-34 based fibrosis score were superior or comparable to the other fibrosis biomarkers and scores. In conclusion, the IL-34 based fibrosis score, including serum IL-34, type IV collagen 7s and age, is a feasible diagnostic marker of liver fibrosis in NAFLD patients.

A tight regulation between the pro- and anti-inflammatory immune responses during plasmodial infection is of crucial importance, since a disruption leads to severe malaria pathology. IL-22 is a member of the IL-10 cytokine family, which is known to be highly important in immune regulation. We could detect high plasma levels of IL-22 in Plasmodium falciparum malaria as well as in Plasmodium berghei ANKA (PbA)-infected C57BL/6J mice. The deficiency of IL-22 in mice during PbA infection led to an earlier occurrence of cerebral malaria but is associated with a lower parasitemia compared to wt mice. Furthermore, at an early time point of infection T cells from PbA-infected Il22(-/-) mice showed an enhanced IFNγ but a diminished IL-17 production. Moreover, dendritic cells from Il22(-/-) mice expressed a higher amount of the costimulatory ligand CD86 upon infection. This finding can be corroborated in vitro since bone marrow-derived dendritic cells from Il22(-/-) mice are better inducers of an antigen-specific IFNγ response by CD8(+) T cells. Even though there is no IL-22 receptor complex known on hematopoietic cells, our data suggest a link between IL-22 and the adaptive immune system which is currently not identified.

CD4(+)CD25(+) T cells are critical for maintenance of immunologic self-tolerance. We measured the number of CD4(+)CD25(+) cells in the patients with primary malignant hypertension related kidney injury, to explore the molecular pathogenesis of this disease. We selected 30 patients with primary malignant hypertension related kidney injury and 30 healthy volunteers. Information on clinical characteristics and laboratory tests was obtained from each subject. The number of CD4(+)CD25(+) cells and glomerular injury were assessed by flow cytometry and histopathology, respectively. Both serum IL-2, IL-4, and IL-6 and endothelial cell markers were analyzed by ELISA. ADAMTS13 antibody was detected by Western blotting. CD4(+)CD25(+) cells were significantly reduced in patients with primary malignant hypertension related kidney injury compared to controls (P < 0.05). The number of CD4(+)CD25(+) cells was negatively related to blood urea nitrogen, serum uric acid, proteinuria, and supernatant IL-4; whereas positively associated with estimated glomerular filtration rate in patients. Gradually decreasing CD4(+)CD25(+) cells were also found as increasing renal injury. Additionally, patients exhibited increasing supernatant IL-4, serum IL-2 and IL-6, endothelial cell markers, and anti-ADAMTS13 antibody compared with controls (all P < 0.05). CD4(+)CD25(+) cells may play a key role in the pathogenesis of primary malignant hypertension related kidney injury.

Myasthenia gravis (MG) is an autoimmunological inflammatory disorder of the neuromuscular junction. Inflammation could be a key player for understanding the pathogenesis of MG. We measured the serum levels of 24 inflammatory cytokines in 43 patients with anti-acetylcholine receptor antibody-positive MG and 25 healthy controls. In patients with MG, serum levels of a proliferation-inducing ligand (APRIL), IL-19, IL-20, IL-28A and IL-35 were significantly increased as compared with controls (p < 0.05). Among them, IL-20, IL-28A and IL-35 were significantly decreased after treatment (p < 0.05). In clinical subtype analyses, APRIL and IL-20 were increased in patients with late-onset MG and IL-28A levels were increased in patients with thymoma-associated MG compared with healthy controls (p < 0.01). The results of the present study demonstrate both anti-inflammatory and inflammatory cytokines are upregulated in MG, reflecting the importance of cytokine-mediated inflammation and its regulation in MG pathophysiology.

HIV-infected slow progressors (SP) represent a heterogeneous group of subjects who spontaneously control HIV infection without treatment for several years while showing moderate signs of disease progression. Under conditions that remain poorly understood, a subgroup of these subjects experience failure of spontaneous immunological and virological control. Here we determined the frequency of SP subjects who showed loss of HIV control within our Canadian Cohort of HIV(+) Slow Progressors and identified the proinflammatory cytokine IL-32 as a robust biomarker for control failure. Plasmatic levels of the proinflammatory isoforms of IL-32 (mainly β and γ) at earlier clinic visits positively correlated with the decline of CD4 T-cell counts, increased viral load, lower CD4/CD8 ratio and levels of inflammatory markers (sCD14 and IL-6) at later clinic visits. We present here a proof-of-concept for the use of IL-32 as a predictive biomarker for disease progression in SP subjects and identify IL-32 as a potential therapeutic target.

Chronic hepatitis C virus (HCV) infection had been associated with cytokine imbalance. Cytokine dynamics in response to peginterferon/ribavirin therapy have an impact on the treatment efficacy for HCV patients. Ninety-two treatment-naive chronic hepatitis C patients were treated with 24 or 48 weeks of peginterferon/ribavirin therapy according to their viral genotypes. Sustained virologic response (SVR) is defined as undetectable HCV RNA throughout a 24-week post-treatment follow-up period. Dynamic serum levels of the following cytokines: (1) Th1-mediated cytokines: IFN-γ, interleukin-2, and TNF-alpha; (2)Th2-mediated cytokines: interleukin-4, interleukin-5, interleukin-6, and interleukin-10 and (3)immuno-modulatory cytokines: interleukin-1β, interleukin-8, and interleukin-12 were determined by Fluorescent Bead immunoassay. Serial dynamic cytokine expression demonstrated that not only elevated IFN-γ concentrations at specific time points but also the total IFN-γ amount was strongly linked to non-response in peginterferon/ribavirin therapy. IFN-γ levels could serve as an independent predictor for SVR analyzed by multivariate logistic regression test. The accuracy of discriminating responders from non-responders was acceptable when IFN-γ cut-off levels were set at 180, 120, and 40 pg/ml at the 4th week, 12th week, and end-of-treatment of therapy, respectively. Elevated on-treatment IFN-γ concentration was significantly associated with treatment failure among interleukin-28B rs8099917TT carriers and those patients failed to achieve rapid virologic response.

Interleukin 31 (IL-31) is a novel T helper type 2 effector cytokine that plays an important role in the pathogenesis of allergic diseases. However, its role in human asthma remains unclear. The aim of this study was to measure IL-31 levels in the serum, bronchoalveolar lavage fluid (BALF) and bronchial tissue of asthmatics and healthy subjects, and identify its possible correlation to disease severity. We quantified IL-31 levels in the serum of patients with asthma (n = 44), as well as in controls (n = 22). Of these subjects, 9 asthmatics and five controls underwent bronchoscopy with endobronchial biopsy and BALF collection. Our data showed that serum and BALF IL-31 levels were significantly elevated in patients with asthma compared with controls. Expressions of IL-31 and IL-31 receptor (IL-31RA and OSMR) were more prominent in the bronchial tissue in severe compared to mild asthma and controls. Serum IL-31 levels correlated positively with Th2 related cytokines (IL-5, IL-13, and TSLP), asthma severity or total serum immunoglobulin E (IgE), and inversely with asthma control and the forced expiratory volume in 1 second (FEV1). The current data may provide insight into the underlying pathogenesis of asthma, in which IL-31 has an important pathogenic role.

The aim of this study was to explore the diagnostic value of IL-31 levels in the pleural fluid and plasma to differentially diagnose tuberculous and malignant pleural effusion. We enrolled 91 cases, including tuberculous pleural effusion (TPE, n = 50), malignant pleural effusion (MPE, n = 41), other cases including pneumonia with pleural fluid, pulmonary tuberculosis and healthy people as controls. Whole blood was stimulated with the M. tuberculosis-specific antigens and plasma was collected. The multiplex bead-based cytokine immunoassay was employed to measure the levels of various cytokines. IL-31 was found to be the most prominent cytokine (P < 0.0001), and with an optimal cut-off value of 67.5 pg/mL, the sensitivity and specificity for the diagnosis of TPE were 86% and 100%, respectively. Furthermore, the tuberculosis-specific IL-31 levels in the plasma of TPE patients were higher than that of MPE patients (P = 0.0002). At an optimal cut-off value of 23.9 pg/mL, the sensitivity and specificity for the diagnosis of TPE were 92.9% and 85.7%, respectively. Ultimately, the combination of pleural fluid with the plasma tuberculosis-specific IL-31 levels improved the sensitivity and specificity to 94.0% and 95.1%, respectively. Thus, we identified a novel biomarker for the diagnosis of TPE for clinical application.

The anti-inflammatory cytokine IL-35 is produced by regulatory T (Treg) cells to suppress autoimmune and inflammatory responses. The role of IL-35 in type 1 diabetes (T1D) remains to be answered. To elucidate this, we investigated the kinetics of Treg cell response in the multiple low dose streptozotocin induced (MLDSTZ) T1D model and measured the levels of IL-35 in human T1D patients. We found that Treg cells were increased in MLDSTZ mice. However, the Treg cells showed a decreased production of anti-inflammatory (IL-10, IL-35, TGF-β) and increased pro-inflammatory (IFN-γ, IL-2, IL-17) cytokines, indicating a phenotypic shift of Treg cells under T1D condition. IL-35 administration effectively both prevented development of, and counteracted established MLDSTZ T1D, seemingly by induction of Eos expression and IL-35 production in Treg cells, thus reversing the phenotypic shift of the Treg cells. IL-35 administration reversed established hyperglycemia in NOD mouse model of T1D. Moreover, circulating IL-35 levels were decreased in human T1D patients compared to healthy controls. These findings suggest that insufficient IL-35 levels play a pivotal role in the development of T1D and that treatment with IL-35 should be investigated in treatment of T1D and other autoimmune diseases.