Vasoactive intestinal peptide promotes host defense against enteric pathogens by modulating the recruitment of group 3 innate lymphoid cells.

Group 3 innate lymphoid cells (ILC3s) control the formation of intestinal lymphoid tissues and play key roles in intestinal defense. They express neuropeptide vasoactive intestinal peptide (VIP) receptor 2 (VPAC2), through which VIP modulates their function, but whether VIP exerts other effects on ILC3 remains unclear. We show that VIP promotes ILC3 recruitment to the intestine through VPAC1 independent of the microbiota or adaptive immunity. VIP is also required for postnatal formation of lymphoid tissues as well as the maintenance of local populations of retinoic acid (RA)-producing dendritic cells, with RA up-regulating gut-homing receptor CCR9 expression by ILC3s. Correspondingly, mice deficient in VIP or VPAC1 suffer a paucity of intestinal ILC3s along with impaired production of the cytokine IL-22, rendering them highly susceptible to the enteric pathogen Citrobacter rodentium This heightened susceptibility to C. rodentium infection was ameliorated by RA supplementation, adoptive transfer of ILC3s, or by recombinant IL-22. Thus, VIP regulates the recruitment of intestinal ILC3s and formation of postnatal intestinal lymphoid tissues, offering protection against enteric pathogens.

IL24 Expression in Synovial Myofibroblasts: Implications for Female Osteoarthritis Pain through Propensity Score Matching Analysis.

(1) Introduction: Despite documented clinical and pain discrepancies between male and female osteoarthritis (OA) patients, the underlying mechanisms remain unclear. Synovial myofibroblasts, implicated in synovial fibrosis and OA-related pain, offer a potential explanation for these sex differences. Additionally, interleukin-24 (IL24), known for its role in autoimmune disorders and potential myofibroblast production, adds complexity to understanding sex-specific variations in OA. We investigate its role in OA and its contribution to observed sex differences. (2) Methods: To assess gender-specific variations, we analyzed myofibroblast marker expression and IL24 levels in synovial tissue samples from propensity-matched male and female OA patients (each n = 34). Gene expression was quantified using quantitative polymerase chain reaction (qPCR). The association between IL24 expression levels and pain severity, measured by a visual analog scale (VAS), was examined to understand the link between IL24 and OA pain. Synovial fibroblast subsets, including CD45-CD31-CD39- (fibroblast) and CD45-CD31-CD39+ (myofibroblast), were magnetically isolated from female patients (n = 5), and IL24 expression was compared between these subsets. (3) Results: Females exhibited significantly higher expression of myofibroblast markers (MYH11, ET1, ENTPD2) and IL24 compared to males. IL24 expression positively correlated with pain severity in females, while no correlation was observed in males. Further exploration revealed that the myofibroblast fraction highly expressed IL24 compared to the fibroblast fraction in both male and female samples. There was no difference in the myofibroblast fraction between males and females. (4) Conclusions: Our study highlights the gender-specific role of myofibroblasts and IL24 in OA pathogenesis. Elevated IL24 levels in females, correlating with pain severity, suggest its involvement in OA pain experiences. The potential therapeutic implications of IL24, demonstrated in autoimmune disorders, open avenues for targeted interventions. Notwithstanding the limitations of the study, our findings contribute to understanding OA's multifaceted nature and advocate for future research exploring mechanistic underpinnings and clinical applications of IL24 in synovial myofibroblasts. Additionally, future research directions should focus on elucidating the precise mechanisms by which IL24 contributes to OA pathology and exploring its potential as a therapeutic target for personalized medicine approaches.

Altered CD4+ T cell and cytokine levels in peripheral blood and skin samples from systemic sclerosis patients and IL-35 in CD4+ T cell growth.

OBJECTIVE: This study explored the role of IL-35 in CD4+ T lymphocyte and human skin fibroblast (HSF) activity and cytokine levels in systemic sclerosis. METHODS: Blood and skin biopsies were collected from 41 patients and 39 healthy controls to assess CD4+ T lymphocytes and IL-35-related factors. CD4+ T lymphocytes were co-cultured with HSFs, recombinant human IL-35 and IL-35 mAb to evaluate the cell viability, activation of CD4+ T lymphocytes and HSF cells. RESULTS: The proportion of blood Th1/Th2 was lower and Th17/Treg was higher in patients than in controls (P < 0.05). IL-35 and IL-17A levels were higher and IFN-γ, IL-10 and TGF-ß levels were lower in patients than in controls. IL-17A, forkhead box P3, TGF-ß1 and collagen type I (COL-1) mRNA and phospho (p)-signal transducer and activator of transcription (STAT) 1 and p-STAT4 were higher in skin tissues from patients than in those from controls (P < 0.05). IL-6 levels were higher, whereas IL-10 levels were lower in cell culture supernatants. α-Smooth muscle actin (α-SMA) and COL-1 proteins and Ki67 positivity were higher in CD4+ T + HSF cells from patients than in those from controls. Recombinant human IL-35 treatment inhibited proliferation (P < 0.001), but increased IL-10 and decreased IL-17A, α-SMA and COL-1 secretion into the conditioned medium of CD4+ T lymphocytes + HSFs from patients compared with those from controls. IL-35 mAb blocked the effects of IL-35 in CD4+ T + HSF cells (P < 0.05). CONCLUSIONS: IL-35 plays an inhibitory role in CD4+ T lymphocyte proliferation but induces Treg cell differentiation by STAT1 signalling activation, HSF proliferation and collagen expression in systemic sclerosis.

Pilot study of fractional microneedling radiofrequency for hidradenitis suppurativa assessed by clinical response and histology.

BACKGROUND: Hidradenitis suppurativa (HS) is a devastating chronic inflammatory skin disease with frequent recurrences. Various systemic treatments and procedures have been used but the efficacy of fractional microneedling radiofrequency (FMR) has not been reported. AIM: To evaluate the clinical and histological efficacy of FMR in the treatment of HS lesions. METHODS: An 8-week, prospective, split-body, unblinded study was conducted, which enrolled 10 adult patients with mild to moderate HS to receive 3 sessions of FMR treatment biweekly. HS severity was assessed using the number and type of lesions, HS Physician Global Assessment (HS-PGA) and the modified Sartorius score (mSS). Skin biopsies were performed on participants to assess change in inflammation before and after FMR. RESULTS: Severity of HS was significantly reduced on the FMR-treated side of the body, but not on the control side. Inflammatory HS lesions were significantly reduced after 4 weeks, while HS-PGA and mSS were significantly decreased after 6 weeks. Immunohistochemistry staining showed decreased expression of inflammatory markers including neutrophil elastases, interleukin (IL)-8 and IL-17, tumour necrosis factor-α, transforming growth factor-ß1 and matrix metalloproteinases. CONCLUSION: FMR may be a viable treatment option for mild to moderate HS.

Interleukin-22 attenuates allergic airway inflammation in ovalbumin-induced asthma mouse model.

BACKGROUND: Allergic asthma is a chronic airway inflammatory disease with a number of cytokines participating in its pathogenesis and progress. Interleukin (IL)-22, which is derived from lymphocytes, acts on epithelial cells and play a role in the chronic airway inflammation. However, the actual role of IL-22 in allergic asthma is still unclear. Therefore, we explored the effect of IL-22 on allergic airway inflammation and airway hyperresponsiveness (AHR) in an ovalbumin (OVA)-induced asthma mouse model. METHODS: To evaluate the effect of IL-22 in an allergic asthma model, BALB/c mice were sensitized and challenged with OVA; then the recombinant mouse IL-22 was administered intranasally 24 h prior to each challenge. The IL-22 levels in lung homogenates and bronchoalveolar lavage fluid (BALF) were measured by enzyme linked immunosorbent assay, respectively. AHR was evaluated through indicators including airways resistance (Rrs), elastance (Ers) and compliance (Crs); the inflammatory cell infiltration was assessed by quantification of differential cells counts in BALF and lung tissues stained by hematoxylin and eosin (H&E); IL-22 specific receptors were determined by immunohistochemistry staining. RESULTS: The concentration of IL-22 was significantly elevated in the OVA-induced mice compared with the control mice in lung homogenates and BALF. In the OVA-induced mouse model, IL-22 administration could significantly attenuate AHR, including Rrs, Ers and Crs, decrease the proportion of eosinophils in BALF and reduce inflammatory cell infiltration around bronchi and their concomitant vessels, compared with the OVA-induced group. In addition, the expression of IL-22RA1 and IL-10RB in the lung tissues of OVA-induced mice was significantly increased compared with the control mice, while it was dramatically decreased after the treatment with IL-22, but not completely attenuated in the IL-22-treated mice when compared with the control mice. CONCLUSION: Interleukin-22 could play a protective role in an OVA-induced asthma model, by suppressing the inflammatory cell infiltration around bronchi and their concomitant vessels and airway hyperresponsiveness, which might associate with the expression of its heterodimer receptors. Thus, IL-22 administration might be an effective strategy to attenuate allergic airway inflammation.

Role of IL-22 in persistent allergic airway diseases caused by house dust mite: a pilot study.

BACKGROUND: Persistent allergic airway diseases cause a great burden worldwide. Their pathogenesis is not clear enough. There is evidence that one of the recently described cytokine interleukin (IL) 22 may be involved in the pathogenesis of these diseases. Scientists argue if this cytokine acts as proinflammatory or anti-inflammatory agent. The aim of this study was to investigate IL-22 level in patients with persistent allergic airway diseases caused by house dust mite (HDM) in comparison with healthy individuals and to evaluate its relationship with IL-13 and IL-10 level, symptoms score and quality of life. METHODS: Patients with persistent allergic rhinitis caused by HDM and having symptoms for at least 2 years with or without allergic asthma were involved into the study. Measurements of IL-22, IL-13 and IL-10 and in serum and nasal lavage was performed by ELISA. Questionnaires assessing symptoms severity and quality of life were used. RESULTS: A tendency was observed that IL-22 in serum and nasal lavage was higher in patients with allergic airway diseases compared to control group (14.86 pg/ml vs. 7.04 pg/ml and 2.67 pg/ml vs. 1.28 pg/ml, respectively). Positive statistically significant correlation was estimated between serum IL-22 and serum IL-10 (rs = 0.57, p < 0.01) and IL-13 (rs = 0.44, p < 0.05) level. Moreover, positive significant correlation was found between IL-22 in nasal lavage and IL-10 in nasal lavage (rs = 0.37, p < 0.05). There was a negative statistically significant correlation between serum IL-22 and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) (rs = - 0.42, p < 0.05). CONCLUSION: Our study showed a possible anti-inflammatory effect of IL-22 in patients with persistent allergic airway diseases caused by HDM.

Interleukin-35 pathobiology in periodontal disease: a systematic scoping review.

BACKGROUND: Interleukin (IL)-35 is a novel anti-inflammatory cytokine that is produced by regulatory T cells. IL-35 mediates immunological functions and plays a protective role in several diseases such as asthma and rheumatoid arthritis. However, the role of IL-35 in gingivitis and periodontitis remains unclear. The aim of this study was to systematically review the literature and collecting the available evidence regarding the role of IL-35 in pathogenesis of periodontal disease. METHODS: A systematic search of electronic databases including MEDLINE, Google Scholar, Cochrane Library, Web of Science, and Scopus was conducted in November 2020 to identify studies addressing the Interleukin-35 pathobiology in periodontal disease. The identified studies were subjected to pre-identified inclusion criteria. The retrived papers were assessed by the authours independently and consensus was reached in cases where disagreement occurred. Articles written in languages other than English, case reports, letters to editors, conference abstracts, theses, and dissertations were excluded from the review. RESULTS: A total of 176 possibly relevant articles were identified through the search strategy. Finally, 15 papers which met the criteria of eligibility were included in this review by consensus. The included articles were classified based on their design and level of evidence.Three subclinical study, ten cross sectional investigation and two randomized clinical trials constituted the final set of studies in this review. At preclinical level, Il-35 showed inhibitory characteristics regarding alveolar bone resorption of animal periodontitis models. The results of observatory human studies confirmed the presence of high levels of IL-35 in saliva, GCF, serum, and gingival biopsies of patients suffering from inflammatory periodontal disease. Moreover, two included clinical trials showed that non-surgical periodontal therapy could downregulate IL-35 production in chronic periodontitis patients. CONCLUSION: Interleukin-35 has an undeniable role in pathobiology of inflammatory periodontal disease. Further well-controlled studies are needed to better elucidate the functional pattern of IL-35 in pathogeneisis of gingival and periodontal disease.

Local and Systemic Expression Profile of IL-10, IL-17, IL-27, IL-35, and IL-37 in Periodontal Diseases: A Cross-sectional Study.

AIM: This study aimed to compare the level of interleukin (IL)-10, IL-17, IL-27, IL-35, and IL-37 in the gingival crevicular fluid (GCF) and human plasma of subjects with periodontal disease. MATERIALS AND METHODS: In this cross-sectional study conducted over a 3-month period at a primary dental clinic in Malaysia, 45 participants were recruited via consecutive sampling and assigned into three groups, namely healthy periodontium group (n = 15), gingivitis group (n = 15), and periodontitis group (n = 15). Gingival crevicular fluid and plasma samples were collected from each participant. Enzyme-linked immunosorbent assay test was conducted to measure the concentration of IL-10, IL-17, IL-27, IL-35, and IL-37. Kruskal-Wallis H test was used to compare the interleukin levels between patient groups. RESULTS: In GCF samples, IL-17 level was the highest in the periodontitis group (p <0.05), while IL-27 was the lowest (p <0.05). Meanwhile, plasma levels of IL-27 and IL-37 were significantly lower (p <0.05) in the periodontitis group, but plasma IL-35 levels were observed to rise with increasing disease severity. CONCLUSION: There are reduced local and systemic levels of IL-27 in periodontitis patients. CLINICAL SIGNIFICANCE: Periodontal diseases exert both local and systemic effects, resulting in the destruction of the tooth-supporting structures and contributing to the systemic inflammatory burden. Some of the cytokines that were investigated in the current study, IL-17, IL-27, IL-35, and IL-37, can be potential biomarkers that warrant further longitudinal clinical studies to determine their usefulness as prognostic/diagnostic markers.

Interleukin-38 in colorectal cancer: a potential role in precision medicine.

Colorectal cancer (CRC) is a leading cause of cancer-related death, partly due to a lack of reliable biomarkers for early diagnosis. To improve the outcome of CRC, it is critical to provide diagnosis at an early stage using promising sensitive/specific marker(s). Using immunohistochemistry and histopathology, IL-38 expression was determined in tissue arrays of CRC with different TNM status and depth of tumour invasion. Data were compared to IL-38 in adjacent non-cancer tissue and correlated with demographic information, including survival. A substantial reduction of IL-38 was detected in the CRC tissue compared to adjacent non-cancer colonic tissue. IL-38 correlated with the extent of tumour differentiation (P < 0.0001); CRC location in the left side of the colon (P < 0.05), and smaller tumour size (≤ 5 cm; P < 0.05). Receiver operating characteristic (ROC) curve analysis demonstrated both high specificity and high sensitivity of IL-38 for the diagnosis of CRC [area under the curve (AUC) = 0.89)]. By sub-group analysis, AUC of IL-38 for the diagnosis of CRC was higher in poorly differentiated, right-sided CRC or tumour size > 5 cm (all AUC > 0.9). Significantly, longer survival was observed for the IL-38high versus the IL-38low groups in CRC patients (P = 0.04). Survival was also longer for IL-38high patients with lymph node metastasis (P = 0.01) and TNM stage III-IV (P = 0.02). Multivariate analysis demonstrated that IL-38 (P = 0.05) and tumour invasion depth (P = 0.04) were independent factors for survival. High IL38 in CRC is an independent prognostic factor for the longer survival of CRC patients. IL-38 signalling may constitute a therapeutic target in CRC.

A randomized trial of Lactobacillus rhamnosus IDCC 3201 tyndallizate (RHT3201) for treating atopic dermatitis.

BACKGROUND: Probiotic therapies, mainly live bacteria, have been proven to be effective in treating atopic dermatitis (AD) with some controversies. Killed probiotics or postbiotics would have immunomodulatory effect in allergic diseases including AD. This study was performed to evaluate the therapeutic effect and safety of tyndallized Lactobacillus rhamnosus (IDCC 3201, isolated from the feces of a Korean breastfed infant, repeated heat-treated and incubated, RHT3201) in children with AD. METHODS: In a randomized, double-blind, placebo-controlled study, RHT3201 at a dose of 1.0 × 1010  CPU/d or placebo was given in children (aged 1-12 years) with moderate AD for 12 weeks. SCORing of AD (SCORAD) scores, allergic inflammatory markers, and safety parameters were evaluated. RESULTS: For evaluating the therapeutic effects of RHT3201, 33 subjects in each group were analyzed. The change of SCORAD total score at 12 weeks (primary outcome) from baseline was significantly greater in the RHT3201 group (-13.89 ± 10.05) compared to the control group (-8.37 ± 9.95). Levels of eosinophil cationic protein (ECP) and interleukin (IL)-31 showed tendency to decrease in the RHT3201 group and significant decreases in subgroup analysis in AD for ≥50 months. For safety analysis, a total of 100 subjects (50 in the treated group and 50 in the control group) were evaluated, and there were no significant differences in safety parameters between two groups. CONCLUSION: In children with moderate AD, oral administration of RHT3201 showed the therapeutic effect on AD, the effects in part correlated with decrement of ECP and IL-31, and the effect was more remarkable in subgroup analysis.

The Association Between Circulating Inflammatory Markers and the Progression of Alzheimer Disease in Norwegian Memory Clinic Patients With Mild Cognitive Impairment or Dementia.

OBJECTIVE: Neuroinflammation may play an important role in the pathogenesis and progression of Alzheimer disease (AD). The aim of the present study was to detect whether increased inflammatory activity at baseline could predict cognitive and functional decline in patients with amnestic mild cognitive impairment (aMCI) or AD dementia after 2 years. METHODS: Serum samples from 242 memory clinic patients with an aMCI (n=88) or AD dementia (n=154) were analyzed for C-reactive protein and for 14 other inflammatory markers [interleukin (IL)-1ß, interleukin-1 receptor antagonist, IL-6, IL-10, IL-12p40, IL-17a, IL-18, IL-22, IL-33, tumor necrosis factor, cluster of differentiation 40 ligand, interferon-γ, chemokine ligand (CCL) 2, and CCL4] by bead-based multiplex immunoassay. Disease progression was measured by the annual increase in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and annual decrease in the score on the Mini-Mental State Examination (MMSE). RESULTS: No association between increased levels of the inflammatory markers and change on the CDR-SB or MMSE score was found, but there was a significant difference in baseline IL-6 and interleukin-1 receptor antagonist levels between aMCI and AD dementia groups. CONCLUSION: Increased levels of inflammatory markers were not associated with faster progression as measured by the annual change on the CDR-SB or MMSE score.

The clinical significance of IL-6 s and IL-27 s in Bronchoalveolar lavage fluids from children with mycoplasma pneumoniae pneumonia.

BACKGROUND: IL-6 was associated with the severity of mycoplasma pneumoniae pneumonia (MPP). But the relationship between IL-27 and MPP was unknown. METHODS: Ninety-eight patients with MPP < 14 years old were enrolled in this study and divided into groups by severity (mild cases and severe cases), infection types (MP single infection group and MP mixed infection group) and DNA loads (low MP DNA loads group and high MP DNA loads group), respectively. Fifteen children with foreign bodies in bronchus were also enrolled as control. IL-6 s and IL-27 s in bronchoalveolar lavage fluids (BALFs) from these children were measured by ELISA. RESULTS: There were significant differences in IL-6 s of BALFs from patients between mild cases and severe cases, MP single infection group and MP mixed infection group, and low MP DNA loads group and high MP DNA loads group, respectively (P < 0.05). Compared with IL-6 s of BALFs from control, IL-6 s in BALFs from the 6 patient groups were significantly higher (P < 0.05). IL-27 s in BALFs from MP mixed infection group were significantly lower than those from MP single infection group and control (P < 0.05) respectively. CONCLUSION: IL-6 was firmly associated with MPP and had potential application in clinical practice while IL-27 was not related to MP infection.

Serum concentrations of IL-31 in dogs with nonpruritic mast cell tumours or lymphoma.

BACKGROUND: The aim of this study was to compare serum interleukin (IL)-31 concentrations in dogs with lymphoma and mast cell tumours (MCT) without pruritus to those of healthy dogs. HYPOTHESIS/OBJECTIVES: To determine if IL-31 plays a role in tumour pathogenesis and if IL-31 could be a biological marker for disease progression. ANIMALS: Forty-eight healthy dogs and 36 dogs with neoplasia [multicentric lymphoma (14), MCT (15) and cutaneous lymphoma (7)] were included in the study. METHODS AND MATERIALS: Dogs with neoplasia were assigned to three different groups. Group 1 consisted of patients with multicentric lymphoma, which were diagnosed by cytological, histopathological and clonality investigations. Thoracic radiographs, ultrasound examination of the abdominal cavity, and fine-needle aspirates from liver and spleen were used to determine the lymphoma stage Patients with cutaneous lymphoma, diagnosed by cytological and histopathological findings, were included in Group 2. Patients with MCT, diagnosed by cytological and histopathological findings, were included in Group 3. Serum was frozen at -80ºC before measuring the concentration of IL-31 via a Simoa ultra-sensitive, fully automated two-step immunoassay. RESULTS: Serum concentrations of IL-31, regardless of the disease and its staging, were within the normal range in all patients; there was no difference between any of the different tumour groups and healthy dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: IL-31 is not likely to be involved in the pathogenesis of canine MCT or lymphoma without pruritus.

"T2-high" in severe asthma related to blood eosinophil, exhaled nitric oxide and serum periostin.

Type-2 (T2) immune responses in airway epithelial cells (AECs) classifies mild-moderate asthma into a T2-high phenotype. We examined whether currently available clinical biomarkers can predict AEC-defined T2-high phenotype within the U-BIOPRED cohort.The transcriptomic profile of AECs obtained from brushings of 103 patients with asthma and 44 healthy controls was obtained and gene set variation analysis used to determine the relative expression score of T2 asthma using a signature from interleukin (IL)-13-exposed AECs.37% of asthmatics (45% nonsmoking severe asthma, n=49; 33% of smoking or ex-smoking severe asthma, n=18; and 28% mild-moderate asthma, n=36) were T2-high using AEC gene expression. They were more symptomatic with higher exhaled nitric oxide fraction (F eNO) and blood and sputum eosinophils, but not serum IgE or periostin. Sputum eosinophilia correlated best with the T2-high signature. F eNO (≥30 ppb) and blood eosinophils (≥300 cells·µL-1) gave a moderate prediction of T2-high asthma. Sputum IL-4, IL-5 and IL-13 protein levels did not correlate with gene expression.T2-high severe asthma can be predicted to some extent from raised levels of F eNO, blood and sputum eosinophil counts, but serum IgE or serum periostin were poor predictors. Better bedside biomarkers are needed to detect T2-high.

Dietary selenium supplementation alleviates immune toxicity in the hearts of chickens with lead-added drinking water.

Lead (Pb) is an environmental pollutant and can damage organisms. Selenium (Se) can alleviate Pb poisoning. The present study aimed to investigate the alleviative effect of Se on Pb-induced immune toxicity in chicken hearts. One-hundred-and-eighty Hy-line male chickens were randomly divided into four groups at 7 days of age. The control group was offered a standard commercial diet (SD) and drinking water (DW); the Se group was offered SD supplemented with sodium selenite (SeSD) and DW; the Pb + Se group was offered SeSD and DW supplemented with lead acetate (PbDW); and the Pb group was offered SD and PbDW. Relative mRNA expression of inducible nitric oxide synthase (iNOS), interleukins (IL-2, IL-4, IL-6, IL-12ß, IL-17 and IFN-γ), and heat shock proteins (HSP27, HSP40, HSP60, HSP70, and HSP90) were determined by means of quantitative real-time PCR. Relative protein expression of iNOS, HSP60, HSP70, and HSP90 was assessed, as well as nitric oxide (NO) content and iNOS activity in heart tissue. The results indicated a down-regulation of interleukin (IL)-2 and IFN-γ and an up-regulation of NO, iNOS, interleukins (IL-4, IL-6, IL-12ß, IL-17), and heat shock proteins (HSP27, HSP40, HSP60, HSP70, and HSP90) in Pb-damaged hearts. Se alleviated all of the above Pb-induced changes. There were time-dependent effects on NO content, iNOS activity, and mRNA levels of iNOS, IL-2, IL-4, IL-6, IL-17, HSP27, HSP40, HSP60, HSP70, and HSP90 after Pb treatment in the chicken hearts. Se alleviated Pb-induced immune toxicity in the chicken hearts.

Interleukin-26 is overexpressed in human sepsis and contributes to inflammation, organ injury, and mortality in murine sepsis.

BACKGROUND: Sepsis is a serious syndrome that is caused by an unbalanced host inflammatory response to an infection. The cytokine network plays a pivotal role in the orchestration of inflammatory response during sepsis. IL-26 is an emerging proinflammatory member of the IL-10 cytokine family with multifaceted actions in inflammatory disorders. However, its role in the pathogenesis of sepsis remains unknown. METHODS: Serum IL-26 level was measured and analyzed in 52 septic patients sampled on the day of intensive care unit (ICU) admission, 18 non-septic ICU patient controls, and 30 healthy volunteers. In addition, the effects of recombinant human IL-26 on host inflammatory response in cecal ligation and puncture (CLP)-induced polymicrobial sepsis were determined. RESULTS: On the day of ICU admission, the patients with sepsis showed a significant increase in serum IL-26 levels compared with ICU patient controls and healthy volunteers, and the serum IL-26 levels were related to the severity of sepsis. Nonsurvivors of septic patients displayed significantly higher serum IL-26 levels compared with survivors. A high serum IL-26 level on ICU admission was associated with 28-day mortality, and IL-26 was found to be an independent predictor of 28-day mortality in septic patients by logistic regression analysis. Furthermore, administration of recombinant human IL-26 increased lethality in CLP-induced polymicrobial sepsis. Despite a lower bacterial load, septic mice treated with recombinant IL-26 had higher concentrations of IL-1ß, IL-4, IL-6, IL-10, IL-17A, TNF-α, CXCL1, and CCL2 in peritoneal lavage fluid and blood and demonstrated more severe multiple organ injury (including lung, liver and kidney) as indicated by clinical chemistry and histopathology. Furthermore, septic mice treated with recombinant human IL-26 showed an increased neutrophil recruitment to the peritoneal cavity. CONCLUSIONS: Septic patients had elevated serum IL-26 levels, which may correlate with disease severity and mortality. In experimental sepsis, we demonstrated a previously unrecognized role of IL-26 in increasing lethality despite promoting antibacterial host responses.

Role of chemical composition and redox modification of poorly soluble nanomaterials on their ability to enhance allergic airway sensitisation in mice.

BACKGROUND: Engineered nanoparticles (NPs) have been shown to enhance allergic airways disease in mice. However, the influence of the different physicochemical properties of these particles on their adjuvant properties is largely unknown. Here we investigate the effects of chemical composition and redox activity of poorly soluble NPs on their adjuvant potency in a mouse model of airway hypersensitivity. RESULTS: NPs of roughly similar sizes with different chemical composition and redox activity, including CeO2, Zr-doped CeO2, Co3O4, Fe-doped Co3O4(using Fe2O3 or Fe3O4) and TiO2 NPs, all showed adjuvant activity. OVA induced immune responses following intranasal exposure of BALB/c mice to 0.02% OVA in combination with 200 µg NPs during sensitization (on day 1, 3, 6 and 8) and 0.5% OVA only during challenge (day 22, 23 and 24) were more pronounced compared to the same OVA treatment regime without NPs. Changes in OVA-specific IgE and IgG1 plasma levels, differential cell count and cytokines in bronchoalveolar lavage fluid (BALF), and histopathological detection of mucosa cell metaplasia and eosinophil density in the conducting airways were observed. Adjuvant activity of the CeO2 NPs was primarily mediated via the Th2 response, while that of the Co3O4 NPs was characterised by no or less marked increases in IgE plasma levels, BALF IL-4 and IL-5 concentrations and percentages of eosinophils in BALF and more pronounced increases in BALF IL-6 concentrations and percentages of lymphocytes in BALF. Co-exposure to Co3O4 NPs with OVA and subsequent OVA challenge also induced perivascular and peribronchiolar lymphoid cell accumulation and formation of ectopic lymphoid tissue in lungs. Responses to OVA combined with various NPs were not affected by the amount of doping or redox activity of the NPs. CONCLUSIONS: The findings indicate that chemical composition of NPs influences both the relative potency of NPs to exacerbate allergic airway sensitization and the type of immune response. However, no relation between the acellular redox activity and the observed adjuvant activity of the different NPs was found. Further research is needed to pinpoint the precise physiological properties of NPs and biological mechanisms determining adjuvant activity in order to facilitate a safe-by-design approach to NP development.

Venoarterial Extracorporeal Membrane Oxygenation Increased Immune Function of Spleen and Decreased Reactive Oxygen Species During Post-Resuscitation.

We aimed to investigate the effect of venoarterial extracorporeal membrane oxygenation (VA-ECMO) on immune function of the spleen and reactive oxygen species (ROS) during post-resuscitation in a porcine model. After 8 min of untreated ventricular fibrillation and 6 min of basic life support, pigs were randomized into two groups: Group 1 received VA-ECMO and Group 2 received conventional cardiopulmonary resuscitation. After successful return of spontaneous circulation, the hemodynamic status was determined and blood samples were collected at 0, 1, 2, 4, and 6 h. Surviving pigs were euthanized 6 h after return of spontaneous circulation, their spleens were harvested and the T-cells were separated. Then, we investigated immune function parameters of the spleen and ROS levels. VA-ECMO increased the return of spontaneous circulation and 6 h survival rate after return of spontaneous circulation. Compared with the conventional cardiopulmonary resuscitation group, the VA-ECMO group showed increased superoxide dismutase and decreased malondialdehyde and ROS levels. Furthermore, VA-ECMO was associated with a high rate of CD4+ and CD4+/CD8+, high levels of interleukin 2, interferon γ, and interferon γ/interleukin 4, as well as high proliferation of lymphocytes. The apoptotic rate of T-cells was lower in the VA-ECMO group than it was in the conventional cardiopulmonary resuscitation group. VA-ECMO increased immune function of spleen and decreased ROS levels during post-resuscitation. Further research is expected to illustrate whether the differences in immune responses are due to ROS or some other perfusion related effect on spleen.

Analysis of Inflammatory Cytokines in Postoperative Fontan Pleural Drainage.

Prolonged pleural drainage is a common complication in patients after Fontan palliation and is associated with short- and long- term morbidities. Among many potential etiologies, prolonged drainage has an inflammatory component, but there are no descriptions of cytokines in Fontan pleural drainage to date. This study aimed to examine the inflammatory make-up of Fontan pleural drainage. This prospective age-range-matched cohort study recruited 25 patients undergoing Fontan procedure and 15 bi-ventricular patients undergoing cardiopulmonary bypass (CPB). Chest tube samples were taken on postoperative day (POD) 1-4, 7, and 10. Cytokines were measured using Bio-Plex Assays. Univariate comparisons were made in patient characteristics and cytokine levels. Median age was 3.7 y (IQR 2.8-3.9) for controls and 2.5 y (IQR 2.1-2.9) in Fontan patients (p = 0.02). Median drainage duration and daily volume was higher in Fontan patients (both p < 0.001). Inflammatory cytokines (IL-17A, IFN-y, MIP-1ß, and TNF-α) were higher in Fontan patients than controls (all p < 0.02). There was an increase in pro-inflammatory cytokines (IL-8, MIP-1ß, and TNF-α) from POD1 to the last chest tube day (LCD) in Fontan patients (all p < 0.0001) and a decrease in the anti-inflammatory cytokine IL-10 (p = 0.001). There was no difference in cytokine concentration from POD1 to LCD among controls. There was a significant association with the cytokine concentration of TNF-α on POD1 and duration of chest tube drainage (p < 0.05). Inflammatory cytokine levels in the pleural fluid of Fontan patients are higher compared to bi-ventricular controls and rise over time where controls do not. This suggests ongoing localized inflammation that is not a result of CPB alone and may be an important contributor to pleural drainage in patients after the Fontan procedure.

Correlation Between IL-20 and De Quervain's Disease Severity.

De Quervain's disease is a stenosing tenosynovitis of the first dorsal compartment of the wrist. Histopathological studies have reported that the thickening of the first dorsal retinaculum is characterized by degeneration rather than inflammation. However, significant infiltration of mast cells and macrophages was noted in a torn tendon study, which suggested that innate immune pathways are part of the mechanism that mediates early tendinopathy. Recently, Interleukin-20 (IL-20) has been reported to provoke potent inflammation and regulate angiogenesis and chemotaxis, which are important for the pathogenesis of inflammatory diseases. The main purpose of our study was to investigate the correlation between IL-20 and tumor necrosis factor (TNF-α) and clarify the potential predictor of tendinopathy progression. Hematoxylin and eosin (H & E) and immunohistochemistry (IHC) staining were used to score and analyze the clinical outcome. TNF-α, IL-20 and related inflammation cytokines were examined. Moreover, the tenocytes were cultured with a stimulator and were used to examine inflammatory cytokine secretions. A real-time polymerase chain reaction (Real-time PCR) was used to detect the gene expression profile. The IHC data showed that TNF-α is up-regulated in grade III de Quervain's. The analysis data showed that IL-20 is positively correlated with TNF-α and disease severity. The real-time PCR showed that the inflammation stimulator enhanced the expression of IL-20 mRNA expression. Inflammation cytokines such as TNF-alpha, transforming growth factor-ß (TGF-ß) and IL-1 have been used as predictors of de Quervain's; IL-20 is a new predictor based on this study. In the future, IL-20 expression's involvement in the molecular mechanism of the severity of de Quervain's should be further investigated.