Adaptive plasticity of natural interleukin-35-induced regulatory T cells (Tr35) that are required for T-cell immune regulation.

Background: IL-35 potently inhibits immune responses both in vivo and in vitro. However, the specific characteristics of IL-35-producing cells, including their developmental origin, cellular phenotype, and function, are unknown. Methods: By using a novel IL-35 reporter mouse (Ebi3-Dre-Thy1.1) and double transgenic fate-mapping reporter mice (35EbiT-Rosa26-rox-tdTomato reporter mice or Foxp3 fate-mapping system), we tracked and analyzed the differentiation and developmental trajectories of Tr35 cells in vivo. And then we investigated the therapeutic effects of OVA-specific Tr35 cells in an OVA-induced allergic airway disease model. Results: We identified a subset of cells, denoted Tr35 cells, that secrete IL-35 but do not express Foxp3. These cells have high expression of molecules associated with T-cell activation and can inhibit T-cell proliferation in vitro. Our analyses showed that Tr35 cells are a distinct subpopulation of cells that are independent of Tr1 cells. Tr35 cells exhibit a unique gene expression profile and tissue distribution. The presence of Thy1.1 (Ebi3) expression in Tr35 cells indicates their active secretion of IL-35. However, the proportion of ex-Tr35 cells (Thy1.1-) is significantly higher compared to Tr35 cells (Thy1.1+). This suggests that Tr35 cells possess the ability to regulate IL-35 expression rapidly in vivo. Tr35 cells downregulated the expression of the inflammatory cytokines IL-4, IFN-γ and IL-17A. However, once Tr35 cells lost IL-35 expression and became exTr35 cells, the expression of inflammatory cytokines was upregulated. Importantly, our findings indicate that Tr35 cells have therapeutic potential. In an OVA-induced allergic airway disease mouse model, Tr35 cell reinfusion significantly reduced airway hyperresponsiveness and histopathological airway and lung inflammation. Conclusions: We have identified a subset of Tregs, Tr35 cells, that are distinct from Tr1 cells. Tr35 cells can dynamically regulate the secretion of inflammatory cytokines by controlling IL-35 expression to regulate inflammatory immune responses.

A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification.

Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.

Interlukin-22 improves ovarian function in polycystic ovary syndrome independent of metabolic regulation: a mouse-based experimental study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a reproductive endocrine disorder with multiple metabolic abnormalities. Most PCOS patients have concomitant metabolic syndromes such as insulin resistance and obesity, which often lead to the development of type II diabetes and cardiovascular disease with serious consequences. Current treatment of PCOS with symptomatic treatments such as hormone replacement, which has many side effects. Research on its origin and pathogenesis is urgently needed. Although improving the metabolic status of the body can alleviate reproductive function in some patients, there is still a subset of patients with metabolically normal PCOS that lacks therapeutic tools to address ovarian etiology. METHODS: The effect of IL-22 on PCOS ovarian function was verified in a non-metabolic PCOS mouse model induced by dehydroepiandrosterone (DHEA) and rosiglitazone, as well as granulosa cell -specific STAT3 knockout (Fshrcre+Stat3f/f) mice (10 groups totally and n = 5 per group). Mice were maintained under controlled temperature and lighting conditions with free access to food and water in a specific pathogen-free (SPF) facility. Secondary follicles separated from Fshrcre+Stat3f/f mice were cultured in vitro with DHEA to mimic the hyperandrogenic environment in PCOS ovaries (4 groups and n = 7 per group) and then were treated with IL-22 to investigate the specific role of IL-22 on ovarian function. RESULTS: We developed a non-metabolic mice model with rosiglitazone superimposed on DHEA. This model has normal metabolic function as evidenced by normal glucose tolerance without insulin resistance and PCOS-like ovarian function as evidenced by irregular estrous cycle, polycystic ovarian morphology (PCOM), abnormalities in sex hormone level. Supplementation with IL-22 improved these ovarian functions in non-metabolic PCOS mice. Application of DHEA in an in vitro follicular culture system to simulate PCOS follicular developmental block and ovulation impairment. Follicles from Fshrcre+Stat3f/f did not show improvement in POCS follicle development with the addition of IL-22. In DHEA-induced PCOS mice, selective ablation of STAT3 in granulosa cells significantly reversed the ameliorative effect of IL-22 on ovarian function. CONCLUSION: IL-22 can improve non-metabolic PCOS mice ovarian function. Granulosa cells deficient in STAT3 reverses the role of IL-22 in alleviating ovary dysfunction in non-metabolic PCOS mice.

Polymorphism of Genes Encoding Inflammatory Interleukins and the Risk of Anterior Cruciate Ligament Injury: A Systematic Review and Meta-Analysis.

Sport injuries, including the anterior crucial ligament rupture (ACLR) seem to be related to complex genetic backgrounds, including the genes responsible for inflammatory response. This review and meta-analysis investigated the contribution of the polymorphisms of genes encoding inflammatory cytokines and their receptors to the risk of ACLR. The scientific databases Science Direct, EBSCO host, Scopus, PubMed, and Google Scholar were screened (completed on 14 June 2023) according to the established inclusion/exclusion criteria (only fully accessible, original, human case-control studies written in English concerning the effect of interleukin genes' polymorphisms on the occurrence of ACL injury were included) and statistical meta-analysis using R version 4.0.3 was performed. The PRISMA methodology was used to review articles. The review protocol was registered under the number CRD42024514316 in the Prospero database. Eighty-nine studies were identified and narrowed down to three original case-control studies used for the meta-analysis. The studies analyzed Polish, South African, and Swedish cohorts, altogether 1282 participants. The candidate polymorphisms indicated in the studies involved IL6 rs1800795, IL6R rs2228145 and IL1B rs16944. The systematic review showed the relationships between IL6 rs1800795 polymorphism and ACLR in the Polish subpopulation, and IL6R rs2228145 and IL1B rs16944 in the South African subpopulations. The meta-analysis revealed that the IL6 rs1800795 CG genotype was over-represented (OR = 1.30, 95% CI 1.02-1.66), while the CC genotype was under-represented (OR = 0.75, 95% CI 0.54-1.03) in ACLR subjects, but no significant impact of IL6R rs2228145 was shown. Additionally, a tendency of the IL1B rs16944 CT genotype to be protective (OR 0.89, 95% CI 0.70-1.14), while the TT to be a risk genotype (OR 1.19, 95% CI 0.84-1.68) was observed. Thus, the relationship between the interleukin receptor IL6R rs2228145 and ACLR risk was not confirmed. However, the impact of genes coding pleiotropic IL6 rs1800795 on the incidences of ACLR was clear and the effect of pro-inflammatory IL1B rs16944 was possible.

The effects of IL-27 and IL-35 gene variation and expression levels on the susceptibility and clinical manifestations of pulmonary tuberculosis.

Inflammatory cytokines have crucial roles in the pathogenesis of tuberculosis (TB), and interleukin (IL)-27 and IL-35 have a pro-inflammatory and anti-inflammatory effect on many diseases, including infectious diseases. Therefore, we evaluated the relationship between IL-27 and IL-35 gene polymorphism, expression levels, and pulmonary TB (PTB) susceptibility. Nine single-nucleotide polymorphisms (SNPs) in the IL-27 gene (rs181206, rs153109, and rs17855750) and the IL-35 gene (rs4740, rs428253, rs9807813, rs2243123, rs2243135, and rs568408) were genotyped by the SNPscan technique in 497 patients with PTB and 501 controls. There was no significant difference regarding the genotype and allele frequencies of the above SNPs in the IL-27 and IL-35 genes between patients with PTB and controls. Haplotype analysis showed that the frequency of the GAC haplotype in the IL-35 gene was significantly decreased in patients with PTB when compared to controls (p = 0.036). Stratified analysis suggested that the frequency of the IL-27 rs17855750 GG genotype was significantly increased in patients with PTB with fever. Moreover, the lower frequency of the IL-35 rs568408 GA genotype was associated with drug-induced liver injury in patients with PTB. The IL-35 rs428253 GC genotype, as well as the rs4740 AA genotype and A allele, showed significant relationships with hypoproteinemia in patients with PTB. When compared with controls, the IL-27 level was significantly increased in patients with PTB. Taken together, IL-35 gene variation might contribute to a protective role on the susceptibility to PTB, and IL-27 and IL-35 gene polymorphisms were associated with several clinical manifestations of patients with PTB.

IL21 inhibits miR-361-5p to promote MAP3K9 and further aggravate the progression of shoulder arthritis.

OBJECTIVE: This research aimed to explore IL-21/miR-361-5p/MAP3K9 expression in shoulder arthritis and identify its regulatory pathways. METHODS: We established a rat shoulder arthritis model, then quantified IL21 and miR-361-5p in synovial fluid using ELISA and monitored the arthritis development. Additionally, IL21's effect on miR-361-5p levels in cultured human chondrocytes (HC-a) was assessed. Chondrocyte cell cycle status and apoptosis were measured via flow cytometry. Interactions between miR-361-5p and MAP3K9 were confirmed through dual-luciferase reporting and bioinformatic scrutiny. Protein levels of MAP3K9, p-ERK1/2, p-NF-κB, MMP1, and MMP9 were analyzed by Western blots. RESULTS: IL21 levels were elevated, while miR-361-5p was reduced in the synovial fluid from arthritic rats compared to healthy rats. IL21 was shown to suppress miR-361-5p in chondrocytes leading to hindered cell proliferation and increased apoptosis. Western blots indicated that miR-361-5p curbed MAP3K9 expression, reducing MMP activity by attenuating the ERK1/2/NF-κB pathway in chondrocytes. CONCLUSION: IL21 upregulation and miR-361-5p downregulation characterize shoulder arthritis, resulting in MAP3K9 overexpression. This chain of molecular events boosts MMP expression in chondrocytes and exacerbates the condition's progression.

Treatment outcome and germline predictive factors of ropeginterferon alpha-2b in myeloproliferative neoplasm patients.

BACKGROUND: Studies have shown that some single nucleotide polymorphisms (SNPs) could serve as excellent markers in foretelling the treatment outcome of interferon (IFN) in myeloproliferative neoplasms (MPN). However, most work originated from western countries, and data from different ethnic populations have been lacking. METHODS: To gain insights, targeted sequencing was performed to detect myeloid-associated mutations and SNPs in eight loci across three genes (IFNL4, IFN-γ, and inosine triphosphate pyrophosphatase [ITPA]) to explore their predictive roles in our cohort of 21 ropeginterferon alpha-2b (ROPEG)-treated MPN patients, among whom real-time quantitative PCR was also performed periodically to monitor the JAK2V617F allele burden in 19 JAK2V617F-mutated cases. RESULTS: ELN response criteria were adopted to designate patients as good responders if they achieved complete hematological responses (CHR) within 1 year (CHR1) or attained major molecular responses (MMR), which occurred in 70% and 45% of the patients, respectively. IFNL4 and IFN-γ gene SNPs were infrequent in our population and were thus excluded from further analysis. Two ITPA SNPs rs6051702 A>C and rs1127354 C>A were associated with an inferior CHR1 rate and MMR rate, respectively. The former seemed to be linked to grade 2 or worse hepatotoxicity as well, although the comparison was of borderline significance only (50%, vs. 6.7% in those with common haplotype, p = 0.053). Twelve patients harbored 19 additional somatic mutations in 12 genes, but the trajectory of these mutations varied considerably and was not predictive of any response. CONCLUSIONS: Overall, this study provided valuable information on the ethnics- and genetics-based algorithm in the treatment of MPN.

Generalized pustular psoriasis in a toddler with IL36RN mutation: a case report.

Generalized Pustular Psoriasis (GPP) is a dermatological autoinflammatory disease that rarely occurs in children and is associated with complex genetic factors. GPP pathogenesis has been associated with mutations in IL36RN gene, which encodes an interleukin-36 receptor antagonist. GPP usually occurs without a history of psoriasis in the patients or their family members. This case report describes the clinical course of a 3-year-old toddler with GPP. The diagnosis of GPP was confirmed through a comprehensive series of examinations, and genetic testing revealed an IL36RN mutation, providing further insight into the genetic basis of the condition. This case highlights the importance of a genetic perspective for diagnosing GPP, particularly in children.

The 5' untranslated region variant rs3811050 C/T of the interleukin-38 encoding gene is associated with susceptibility to rheumatoid arthritis in Iraqi women.

BACKGROUND: Interleukin (IL)-38, the latest member of the IL-1 cytokine family, is proposed to have a pathogenic role in rheumatoid arthritis (RA). It is encoded by the IL1F10 gene, which harbors single nucleotide polymorphisms (SNPs) that may predict the risk of autoimmune diseases. Among them are 5' untranslated region (UTR) SNPs, which play a key role in post-transcriptional control, but have not been studied in Iraqi RA patients. METHODS: Two novel IL1F10 5'UTR SNPs (rs3811050 C/T and rs3811051 T/G) were explored in RA and control women (n = 120 and 110, respectively). SNPs were genotyped using TaqMan assay. An ELISA kit was used to measure serum IL-38 concentrations. RESULTS: A reduced risk of RA was associated with rs3811050 T allele and CT genotype (corrected probability [pc] = 0.01 and < 0.001, respectively), while there was no significant association with rs3811051. Haplotype analysis demonstrated that C-T haplotype was associated with a 1.65-fold greater risk of RA, whereas a reduced risk was linked to T-G haplotype. IL-38 concentrations were higher in patients than in controls (p < 0.001). In addition, IL-38 showed acceptable performance in distinguishing between RA and control women (p < 0.001). When IL-38 concentrations were stratified according to SNP genotypes, no significant differences were found. CONCLUSIONS: The rs3811050 variant was more likely to affect RA susceptibility in Iraqi women, and the T allele may play a role in reducing disease risk. IL-38 concentrations were elevated in RA patients, but were not affected by the rs3811050 and rs3811051 genotypes.

Dissecting the respective roles of microbiota and host genetics in the susceptibility of Card9-/- mice to colitis.

BACKGROUND: The etiology of inflammatory bowel disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown. RESULTS: Card9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3ß and Reg3γ independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that 5 weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups' own genotype. CONCLUSIONS: These results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or "healthy" microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders. Video Abstract.

IL-22-dependent responses and their role during Citrobacter rodentium infection.

The mouse pathogen Citrobacter rodentium is utilized as a model organism for studying infections caused by the human pathogens enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) and to elucidate mechanisms of mucosal immunity. In response to C. rodentium infection, innate lymphoid cells and T cells secrete interleukin (IL)-22, a cytokine that promotes mucosal barrier function. IL-22 plays a pivotal role in enabling mice to survive and recover from C. rodentium infection, although the exact mechanisms involved remain incompletely understood. Here, we investigated whether particular components of the host response downstream of IL-22 contribute to the cytokine's protective effects during C. rodentium infection. In line with previous research, mice lacking the IL-22 gene (Il22-/- mice) were highly susceptible to C. rodentium infection. To elucidate the role of specific antimicrobial proteins modulated by IL-22, we infected the following knockout mice: S100A9-/- (calprotectin), Lcn2-/- (lipocalin-2), Reg3b-/- (Reg3ß), Reg3g-/- (Reg3γ), and C3-/- (C3). All knockout mice tested displayed a considerable level of resistance to C. rodentium infection, and none phenocopied the lethality observed in Il22-/- mice. By investigating another arm of the IL-22 response, we observed that C. rodentium-infected Il22-/- mice exhibited an overall decrease in gene expression related to intestinal barrier integrity as well as significantly elevated colonic inflammation, gut permeability, and pathogen levels in the spleen. Taken together, these results indicate that host resistance to lethal C. rodentium infection may depend on multiple antimicrobial responses acting in concert, or that other IL-22-regulated processes, such as tissue repair and maintenance of epithelial integrity, play crucial roles in host defense to attaching and effacing pathogens.

Expression and function of cytokine interleukin-22 gene in the tumor microenvironment of triple negative breast cancer.

BACKGROUND: The tumor microenvironment (TME) and interleukin-22 (IL-22) in cytokines have recently attracted much attention due to their potential impact on tumor biology. However, the role of IL-22 in triple negative breast cancer (TNBC) TME is still poorly understood. This article investigated the gene expression and function of IL-22 in TNBC TME. METHODS: Tumor samples from TNBC patients were collected, and adjacent noncancerous tissues were used as controls. A functional test was performed to evaluate the impact of IL-22 for TNBC cells, including proliferation, migration, and apoptosis. RESULTS: IL-22 gene expression in TNBC tumor samples was markedly higher relative to adjacent non-cancerous tissues (P < 0.05). In addition, it was also observed that IL-22facilitated proliferation and migration of TNBC cells, and inhibit apoptosis. This article reveals the role of IL-22 in the TME of TNBC. The up-regulation of IL-22 gene expression in TNBC tumors and its promoting effect on cancer cell invasiveness highlight its potential as a therapeutic target in TNBC treatment strategies. CONCLUSION: The findings suggested that targeting IL-22 and its related pathways can offer new insights for developing effective therapies for TNBC.

Acquired diffuse palmoplantar erythema with keratoderma in Chinese patients with pustular psoriasis: A predictor for IL36 receptor antagonist c.115+6T>C mutation?

Several studies have suggested that mutation of the interleukin 36 receptor antagonist gene (IL36RN) is related to generalized pustular psoriasis (GPP), and the presence of IL36RN mutation may affect the clinical manifestations and treatment responses. However, genetic testing is not routinely available in clinical practice for the diagnosis of GPP. Previously, GPP patients with acrodermatitis continua of Hallopeau (ACH) were found to have a high percentage of carrying IL36RN mutation. In this study, we reported six patients with pustular psoriasis presenting as diffuse palmoplantar erythema with keratoderma among 60 patients who carried IL36RN mutation. ACH was present in five patients and five patients had acute flare of GPP. This unique presentation may serve as a predictor for IL36RN mutation in patients with pustular psoriasis, similar to ACH.

Interleukin gene polymorphisms and alopecia areata: A systematic review and meta-analysis.

BACKGROUND: Alopecia areata (AA) is an autoimmune disease which results in non-scarring hair loss on the scalp or any surface with hair. Several genetic polymorphisms of the interleukin genes have been linked with this disease but the results are inconsistent. This systematic review and meta-analysis were done to find the association between rs3118470, rs2275913, rs3212227, and rs10889677 of the IL2RA, IL17A, IL12B, and IL23R genes, respectively, of the interleukin family with alopecia areata. METHODS: A comprehensive search for relevant research articles was conducted in Pubmed, Google Scholar, and Embase databases. Our search yielded 8 relevant articles with 1940 cases and 1788 controls. The odds ratio with 95% confidence intervals was calculated using fixed effect and random effect models. Heterogeneity was determined using the Q-test and I2 test. Publication bias was determined and funnel plots were used to adjust the odds ratio. RESULTS: We found a significant risk effect for rs3118470 of the IL2RA gene with alopecia areata in the dominant model (CC + CT vs TT; OR = 1.54, 95% confidence interval = 1.05-2.26, P < .05, I2 = 69.03%) and homozygous model (CC vs TT; OR = 2.00, 95% confidence interval = 1.07-3.71, P < .05, I2 = 72.84%). For the other single nucleotide polymorphisms, we could not find any statistically significant association with the disease. CONCLUSION: Our analysis showed that mutation of rs3118470 of IL2RA gene possesses a significant risk effect for alopecia areata. Future studies with larger sample sizes and ethnic backgrounds are warranted to confirm our findings.

PIKFYVE inhibitors trigger interleukin-24-dependent cell death of autophagy-dependent melanoma.

Inhibitors specifically targeting the 1-phosphatidylinositol 3-phosphate 5-kinase (PIKFYVE) disrupt lysosome homeostasis, thereby selectively terminating autophagy-dependent human cancer cells in vivo as well as in vitro without harming the viability of nonmalignant cells. To elucidate the mechanism by which PIKFYVE inhibition induces cell death, autophagy-dependent melanoma cells were compared with normal foreskin fibroblasts. RNA sequence profiling suggested that PIKFYVE inhibitors upregulated an endoplasmic reticulum (ER) stress response involving interleukin-24 (IL24; also known as MDA7) selectively in melanoma cells. Subsequent biochemical and genetic analyses confirmed these results and extended them to tumor xenografts in which tumor formation and expansion were inhibited. IL24 expression was upregulated by the DDIT3/CHOP/CEBPz transcription factor, a component of the PERK-dependent ER-stress response. Ectopic expression of IL24-induced cell death in melanoma cells, but not in foreskin fibroblasts, whereas ablation of the IL24 gene in melanoma cells prevented death. IL24 upregulation was triggered specifically by PIKFYVE inhibition. Thus, unlike thapsigargin and tunicamycin, which induce ER-stress indiscriminately, PIKFYVE inhibitors selectively terminated PIKFYVE-sensitive melanoma by inducing IL24-dependent ER-stress. Moreover, induction of cell death by a PIKFYVE inhibitor together with ectopic expression of IL24 protein was cumulative, thereby confirming the therapeutic potential of PIKFYVE inhibitors in the treatment of melanoma.

IL-38 in Behçet's disease: Gene expression in bronchoalveolar lavage from patients having pulmonary involvement.

The etiological complexity of Behçet disease (BD), an immune-mediated rare form of vasculitis characterized by multi-organ involvement, is still elusive due to an incomplete understanding of the synergy between genetic susceptibility, environmental triggers, and an abnormal immune response. The diagnosis of BD relies on clinical symptoms. Lung inflammatory disorders are severe conditions of patients with BD, here we focus on the expression of biomarkers in BD patients with pulmonary manifestations. Aiming to identify additional discriminating biomarker patterns, we measured and compared protein and gene expression of IL-38 and a broad panel of selected genes in bronchoalveolar cells of patients suffering from BD with and without pulmonary involvement compared to controls. ELISA and RT-PCR analysis were applied. The first principal analysis highlighted decreased IL-38 level in BD patients compared to Rheumatoid Arthritis (RA) patients and controls: BD patients expressed lower IL-38 levels, particularly in cases with pulmonary involvement. The area under the curve (AUC) of the receiver-operating characteristic curve showed that IL-38 may be an eventual biomarker for BD. Co-cultured recombinant IL-38 and stimulated memory PBMCs of active BD, were able to suppress IL-17 and NLRP3 inflammasome and ameliorate the secretion of IL-10 and TGFß. Transcription factors of the IL-1 family (IL-1ß, IL-18, IL-32, IL-33 and IL-37) along with IFN-γ, IL-17, RORγt, Foxp3, TGFß, IL-10 and NLRP3 inflammasome were the parameters that are the main contributor to the segregation between BD with and without lung involvement. Our results indicate that IL-38 might be involved in the pathogenesis of BD and the combined gene expression in BAL suggests distinct mechanisms governing the inflammatory disorders in the lung.

Interleukin-19 enhances eosinophil infiltration through upregulation of epithelium-derived RANTES expression via the ERK/NF-κB signalling pathway in patients with eosinophilic CRSwNP.

BACKGROUD: The recurrence rate of chronic rhinosinusitis with nasal polyps (CRSwNP) is positively correlated with eosinophil infiltration. Increased interleukin (IL)-19 and eosinophil chemokine RANTES levels have been reported in patients with CRSwNP. This study aimed to clarify the role of IL-19 in mediating RANTES expression and eosinophilic infiltration in eosinophilic CRSwNP (Eos CRSwNP). METHODS: Nasal tissue samples were obtained from patients with CRSwNP and controls. The expression of IL-19, its receptors, ECP, and RANTES in tissues was investigated. Primary human nasal epithelial cells (HNECs) and nasal polyp tissue blocks were cultured, then stimulated by IL-19; ERK phosphorylation, NF-κB pathway activation, RANTES level, eosinophils migration and infiltration were detected using RT-qPCR, ELISA, western blotting, HE, immunohistochemistry, immunofluorescence staining, confocal microscopy, and transwell migration assay. RESULTS: The expression of IL-19 and its receptors (IL-20R1/IL-20R2), eosinophil cationic protein, and RANTES in nasal tissues from patients with Eos CRSwNP was significantly increased compared to that in non-Eos CRSwNP and control subjects. IL-19 co-localized with RANTES in nasal tissues and significantly elevated RANTES expression in HNECs. IL-19-blocking antibody and siRNA knockdown of IL-20R1 ameliorated the effect of IL-19 on RANTES secretion in HNECs. Moreover, IL-19-induced RANTES upregulation was associated with the activation of the ERK and NF-κB pathways. NF-κB activation was mediated by the ERK pathway in IL-19-treated HNECs, and IL-19 enhanced eosinophil infiltration in nasal polyp tissue blocks. CONCLUSIONS: Our findings indicate that IL-19 promotes RANTES expression via the ERK/NF-κB pathway in HNECs and is implicated in eosinophil infiltration in patients with Eos CRSwNP.

Increased neutrophil-derived IL-17A identified in generalized pustular psoriasis.

Generalized pustular psoriasis (GPP) is considered to be a distinct clinical entity from psoriasis vulgaris (PV), with different clinical and histological manifestations. The pathogenesis of GPP has not been thoroughly elucidated, especially in those patients lacking interleukin (IL)36RN. In present study, we performed RNA sequence analysis on skin lesions from 10 GPP patients (4 with and 6 without IL36RN mutation) and 10 PV patients without IL36RN mutation. Compared with PV, significantly overexpressed genes in GPP patients were enriched in IL-17 signalling pathway (MMP1, MMP3, DEFB4A and DEFB4B, etc.) and associated with neutrophil infiltration (MMP1, MMP3, ANXA and SERPINB, etc.). GPP with IL36RN mutations evidenced WNT11 upregulation and IL36RN downregulation in comparison to those GPP without IL36RN mutations. The expression of IL-17A/IL-36 in skin or serum and the origin of IL-17A in skin were also investigated. IL-17A expression in skin was significantly higher in GPP than PV patients, whereas, there were no differences in skin IL-36α/IL-36γ/IL-36RA or serum IL-17A/IL-36α/IL-36γ between GPP than PV. Besides, double immunofluorescence staining of MPO/IL-17A or CD3/IL-17A further confirmed that the majority of IL-17A in GPP skin was derived from neutrophils, but not T cells. These data emphasized the role of neutrophil-derived IL-17A in the pathogenesis of GPP with or without IL36RN mutations. Targeting neutrophil-derived IL-17A might be a promising treatment for GPP.

Interleukin-6 And Interleukin-10 Polymorphisms In Chronic Lymphoid Leukemia Patients.

OBJECTIVE: A major part of the cytokines secreted from the immune system are interleukins (IL) and their main role is to stimulate the immune system cells. Therefore the genotypic effects of IL-6 and IL-10 on the immune system in CLL were investigated in the study. METHOD: For this purpose 100 patients diagnosed with CLL and 70 healthy individuals with no cancer history were included in the study. Polymorphisms at IL10 and IL 6 promoter regions (1082 A\G and 819 C\T) and IL6 (174 G\C) polymorphisms were analyzed with RT-PCR. Genotype and allele frequencies were directly calculated. RESULT: In 100 CLL patients, 45 wild type AA, 40 AG and 15 mutant type GG genotypes were found for the IL 10 1082 A\G region. Genotypic distribution of IL10 819 C\T region was determined as CC, BT and TT genotypes in 37, 50 and 13 patients, respectively. In IL 6 174 G\C region, GG, GC and CC genotypes were determined in 62, 30 and 8 patients, respectively. There is no statistically significant difference between the CLL patients and control groups in terms of IL10 1082 A\G, 819 C\T and IL 6 174 G/C regions (p> 0.05). As a result of the allele frequency calculation of the IL 10 1082 region, the values obtained were A (0.65), G (0.35) for the patient group and (0.61) and G (0.31) for the control group. 819 region allele frequencies were C (0.57) and T (0.33) in the patient group and C (0.48) and T (0.32) in the control group. The IL6 174 region was calculated as G (0.82), C (0.28) in the patient group and G (0.63), C (0.23) in the control group. Given the number of patients within the limits of this study, IL 10 and IL 6 genotype frequencies do not seem to be statistically related to CLL patients. CONCLUSION: Mutant alleles of all interleukin SNPs were determined at a higher frequency in the patient group as compared to the control group. Therefore, a potential correlation between the SNPs of these interleukins and CLL can be determined in future studies with a higher number of samples.

IL32 downregulation lowers triglycerides and type I collagen in di-lineage human primary liver organoids.

Steatotic liver disease (SLD) prevails as the most common chronic liver disease yet lack approved treatments due to incomplete understanding of pathogenesis. Recently, elevated hepatic and circulating interleukin 32 (IL-32) levels were found in individuals with severe SLD. However, the mechanistic link between IL-32 and intracellular triglyceride metabolism remains to be elucidated. We demonstrate in vitro that incubation with IL-32ß protein leads to an increase in intracellular triglyceride synthesis, while downregulation of IL32 by small interfering RNA leads to lower triglyceride synthesis and secretion in organoids from human primary hepatocytes. This reduction requires the upregulation of Phospholipase A2 group IIA (PLA2G2A). Furthermore, downregulation of IL32 results in lower intracellular type I collagen levels in di-lineage human primary hepatic organoids. Finally, we identify a genetic variant of IL32 (rs76580947) associated with lower circulating IL-32 and protection against SLD measured by non-invasive tests. These data suggest that IL32 downregulation may be beneficial against SLD.