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.

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.

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-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 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.

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.

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.

IFNL1 rs30461 polymorphism as a risk factor for COVID-19 severity: A cross-sectional study.

INTRODUCTION: The molecular basis of the progression of some COVID-19 patients to worse outcomes is not entirely known. Interferons-lambda-1/interleukin-29 (IFN-λ1/IL-29) is a member of the type III IFNs with a strong antiviral activity. Given the scant data on the potential role of IFN-λ1/IL-29 in COVID-19, we investigated the association of IFN-λ1/IL-29 serum level and the IFNL1 single-nucleotide polymorphism (SNP) (rs30461) with severe course of COVID-19. MATERIAL AND METHODS: This cross-sectional study included 400 COVID-19 patients, in which 262 mild COVID-19 patients and 138 severe COVID-19 patients were recruited and compared. The IFN-λ1/IL-29 serum levels were assessed in both the mild and severe COVID-19 groups. All participants were genotyped for the IFNL1 SNP (rs30461) by allelic discrimination RT-PCR using specific Taqman probes and primers. The associations between IFNL1 variants and risk of severe COVID-19 were examined via the logistic regression analysis. RESULTS: The serum IFN-λ1/IL-29 levels showed no statistically significant difference between mild and severe COVID-19 patients (P = 0.993). The genotype and allele frequencies of IFNL1 SNP (rs30461) were significantly different between the mild and severe groups, in which the minor G allele carried a highly significant risk of severe COVID-19 compared with the wild A allele [OR (95 %CI): 2.1 (1.5-2.9), P ≤ 0.001]. In multivariate analysis, the A/G and G/G genotypes of IFNL1 SNP (rs30461) were independent predictors of COVID-19 severity (P < 0.05). CONCLUSION: The study concluded that the IFNL1 SNP (rs30461) may constitute an independent risk factor for COVID-19 severity.

Interleukin 28A aggravates Con A-induced acute liver injury by promoting the recruitment of M1 macrophages.

Immune-mediated acute hepatic injury is characterized by the destruction of a large number of hepatocytes and severe liver function damage. Interleukin-28A (IL-28A), a member of the IL-10 family, is notable for its antiviral properties. However, despite advances in our understanding of IL-28A, its role in immune-mediated acute injury remains unclear. The present study investigated the role of IL-28A in concanavalin A (Con A)-induced acute immune liver injury. After Con A injection in mice, IL-28A level significantly increased. IL-28A deficiency was found to protect mice from acute liver injury, prolong survival time, and reduce serum aspartate aminotransferase and alanine aminotransferase levels. In contrast, recombinant IL-28A aggravated liver injury in mice. The proportion of activated M1 macrophages was significantly lower in the IL-28A-deficiency group than in the wild-type mouse group. In adoptive transfer experiments, M1 macrophages from WT could exacerbate mice acute liver injury symptoms in the IL-28A deficiency group. Furthermore, the expression of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), IL-12, IL-6, and IL-1ß, by M1 macrophages decreased significantly in the IL-28A-deficiency group. Western blotting demonstrated that IL-28A deficiency could limit M1 macrophage polarization by modulating the nuclear factor (NF)-κB, mitogen-activated protein kinase (MAPK), and interferon regulatory factor (IRF) signaling pathways. In summary, IL-28A deletion plays an important protective role in the Con A-induced acute liver injury model and IL-28A deficiency inhibits the activation of M1 macrophages by inhibiting the NF-κB, MAPK, and IRF signaling pathways. These results provide a potential new target for the treatment of immune-related hepatic injury.

Genetic association of circulating interleukins and risk of colorectal cancer: A bidirectional Mendelian randomization study.

BACKGROUND: Previous studies have reported that inflammation, especially interleukin family members, plays an important role in the development of colorectal cancer (CRC). However, because of various confounders and the lack of clinical randomized controlled trial, the causal relationship between genetically predicted level of interleukin family and CRC risk has not been fully explained. OBJECTIVE: Bi-directional Mendelian randomization (MR) was conducted to investigate the causal association between interleukin family members and CRC. METHODS: Several genetic variables were extracted as instrumental variables (IVs) from summary data of genome-wide association studies (GWAS) for interleukin and CRC. IVs of interleukin family were obtained from recently published GWAS studies and the summary data of CRC was from FinnGen Biobank. After a series of quality control measures and strict screening, six models were used to evaluate the causal relationship. Pleiotropy, heterogeneity test, and a variety of sensitivity analysis were also used to estimate the robustness of the model results. RESULTS: Genetically predicted higher circulating levels of IL-2 (odds ratio [OR]: 0.76; 95% confidence interval [CI]: 0.63-0.92; p = .0043), IL-17F(OR: 0.78; 95% CI: 0.62-1.00; p = .015), and IL-31 (OR: 0.88; 95% CI: 0.79-0.98; p = .023) were suggestively associated with decreased CRC risk. However, higher level of IL-10 (OR: 1.40; 95% CI: 1.18-1.65; p = .000094) was causally associated with increased risk of CRC. Reverse MR results indicated that the exposure of CRC was suggestively associated with higher levels of IL-36α (OR: 1.23; 95% CI: 1.01-1.49; p = .040) and IL-17RD (OR: 1.22; 95% CI, 1.00-1.48; p = .048) and lower level of IL-13 (OR: 0.78; 95% CI: 0.65-0.95; p = .013). The overall MR results did not provide evidence for causal relationships between other interleukins and CRC (p > .05). CONCLUSION: We offer suggestive evidence supporting a potential causal relationship between circulating interleukins and CRC, underscoring the significance of targeting circulating interleukins as a strategy to mitigate the incidence of CRC.

Interleukin 21 Drives a Hypermetabolic State and CD4+ T-Cell-Associated Pathogenicity in Chronic Intestinal Inflammation.

BACKGROUND & AIMS: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. METHODS: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn's disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4+ T-cell-induced murine colitis models. RESULTS: Mitochondria-endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria-endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 ß, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 ß pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r-/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. CONCLUSIONS: IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4+ T-cell-driven chronic intestinal inflammation.

Spesolimab, A Novel Interleukin-36 Inhibitor for Generalized Pustular Psoriasis Flares in Adult Patients.

Generalized pustular psoriasis (GPP) is a rare, immune-mediated inflammatory disease with characteristic cutaneous and systemic manifestations. Mutations in the interleukin-36 receptor antagonist (IL36RN) gene have been implicated in its pathogenesis. Spesolimab is a novel systemic biologic therapy that selectively inhibits interleukin-36. It was recently approved by Health Canada and the US FDA for the treatment of GPP flares in adults. Results from phase 1 and 2 studies have been promising. Herein, we review the efficacy and safety of spesolimab for the treatment of GPP flares, as demonstrated in clinical trials.

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.

Human interleukin-36γ plays a crucial role in cytokine induction during Sporothrix brasiliensis and S. schenckii infection in keratinocytes and PBMCs.

Cytokines of the interleukin (IL)-1 superfamily including the different IL-36 isoforms, have been reported as mediators of acute and chronic inflammation in human skin diseases, such as psoriasis. Here, we demonstrated for the first time that Sporothrix schenckii and S. brasiliensis, the fungi that cause subcutaneous infection sporotrichosis, can induce the expression of IL-36α, IL-36γ and IL-36Ra in human keratinocytes and primary peripheral blood mononuclear cells (PBMCs). Specifically, IL-36γ was differentially expressed by keratinocytes stimulated with Sporothrix yeasts when compared to the commensal microorganism Staphylococcus epidermidis. The exposure of keratinocytes to 24 h or 7-days culture supernatant of PBMCs stimulated with Sporothrix induced higher IL-36γ production compared to direct stimulation of keratinocytes with the live fungus. We identified that IL-36γ mRNA expression in keratinocytes is increased in the presence of IL-17, TNF, IL-1ß and IL-1α and these cytokines may act synergistically to maintain IL-36γ production. Lastly, using a cohort of 164 healthy individuals, we showed that individuals carrying variants of the IL36G gene (rs11690399 and rs11683399) exhibit increased IL-36γ production as well as increased innate cytokine production after Sporothrix exposure. Importantly, stimulation of PBMCs with recombinant IL-36γ increased the production of IL-1ß and IL-6, while IL-36Ra were able to decrease the concentration of these cytokines. Our findings contribute to the understanding of the pathogenesis of sporotrichosis and suggest that IL-36γ may be involved in maintaining the cytokine loop that leads to tissue destruction by exacerbating the immune response in sporotrichosis. Of high interest, we present the IL-36 signalling pathway as a potential new therapeutic target.

Molecular landscape of the interleukin-40 encoding gene, C17orf99, in patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is a malignant hematological disorder in which aberrant cytokine signaling and inflammation play a role in disease initiation and progression. Interleukin-40 (IL-40) is a novel cytokine encoded by the chromosome 17 open reading frame 99 (C17orf99) gene. This cytokine is involved in mediating inflammation but its biological significance in the pathogenesis of AML has not been investigated. In this case-control and observational study, mRNA expression and DNA methylation of the C17orf99 gene were evaluated in the peripheral blood of AML patients. In addition, the polymorphism of two novel intergenic variants of the C17orf99 gene, rs2004339 A/G and rs2310998 G/A, were explored using a real-time polymerase chain reaction assay. The study was conducted on 131 patients with AML and 106 controls and gene expression and DNA methylation were expressed as fold-change (2-ΔΔCt). Results revealed that mRNA expression of the C17orf99 gene was down-regulated in AML patients, particularly in females, while up-regulated expression was found in patients with hypoalbuminemia. For DNA methylation, it was up-regulated in AML patients, particularly in females, AML M5 subtype, and CD4-negative and CD14-positive peripheral blood cells. The mutant A allele and the corresponding homozygous AA genotype of rs2004339 was significantly associated with an increased risk of AML. The AA genotype was also associated with significantly up-regulated C17orf99 mRNA expression and DNA methylation of compared to the wild-type GG genotype. In conclusions, C17orf99 mRNA expression showed down-regulated levels in the peripheral blood of AML patients, while DNA methylation was up-regulated. The intergenic variant rs2004339 was associated with susceptibility to AML and had an effect on mRNA expression and DNA methylation.

Tumor-derived interleukin 35 mediates the dissemination of gemcitabine resistance in pancreatic adenocarcinoma.

Rapid development of drug resistance after chemotherapy is a major cause of treatment failure in individuals with pancreatic ductal adenocarcinoma (PDAC). In this study, we illustrate that tumor-derived interleukin 35 (IL-35) mediates the accelerated resistance of PDAC to gemcitabine (GEM). We observe that GEM resistance can spread from GEM-resistant PDAC cells to GEM-sensitive cells, and that IL-35 is responsible for the propagation of chemoresistance, which is supported by sequencing and experimental data. Additionally, we discover that GEM-resistant cells have significantly higher levels of IL-35 expression. Mechanistically, aberrantly expressed IL-35 triggers transcriptional activation of SOD2 expression via GP130-STAT1 signaling, scavenging reactive oxygen species (ROS) and leading to GEM resistance. Furthermore, GEM treatment stimulates IL-35 expression through activation of the NF-κB pathway, resulting in acquired chemoresistance. In the mouse model, a neutralizing antibody against IL-35 enhances the tumor suppressive effect of GEM. Collectively, our data suggests that IL-35 is critical in mediating GEM resistance in pancreatic cancer, and therefore could be a valuable therapeutic target in overcoming PDAC chemoresistance.

Cutaneous findings and treatments in deficiency of interleukin-36 receptor antagonist (DITRA): A review of the literature.

Deficiency of the interleukin-36 receptor antagonist (DITRA) is a rare autoinflammatory disorder caused by mutations in the IL36RN gene. This mutation leads to a lack of functional interleukin-36 receptor antagonists (IL-36Ra), which results in an overactive immune system and chronic inflammation. Despite its rarity, numerous case series and individual reports in the literature emphasize the importance of recognizing and managing DITRA. Early identification of the cutaneous signs of DITRA is crucial for accurate diagnosis and timely administration of appropriate treatment. This review article provides a comprehensive overview of the current understanding of the cutaneous, non-cutaneous and histopathological manifestations of DITRA, with a focus on reported treatments. The disease typically presents in early childhood, although the age of onset can vary. Patients with DITRA exhibit recurrent episodes of skin inflammation, often with a pustular or pustular psoriasis-like appearance. Additionally, non-cutaneous manifestations are common, with recurrent fevers and elevated acute-phase reactants being the most prevalent. The exact prevalence of DITRA is unknown. Some cases of loss-of-function mutations in the IL36RN gene, considered a hallmark for diagnosis, have been identified in patients with familial generalized pustular psoriasis (GPP). Biological therapies with inhibition of IL-12/23 and IL-17 are promising treatment options; paediatric patients with DITRA have shown complete response with mild relapses. New and emerging biologic therapeutics targeting the IL-36 pathway are also of interest in the management of this rare autoinflammatory disorder.

Targeting fusion proteins of the interleukin family: A promising new strategy for the treatment of autoinflammatory diseases.

As a means of communication between immune cells and non-immune cells, Interleukins (ILs) has the main functions of stimulating the proliferation and activation of inflammatory immune cells such as dendritic cells and lymphocytes, promote the development of blood cells and so on. However, dysregulation of ILs expression is a major feature of autoinflammatory diseases. The drugs targeting ILs or IL-like biologics have played an important role in the clinical treatment of autoinflammatory diseases. Nevertheless, the widespread use of IL products may result in significant off-target adverse reactions. Thus, there is a clear need to develop next-generation ILs products in the biomedical field. Fusion proteins are proteins created through the joining of two or more genes that originally coded for separate proteins. Over the last 30 years, there has been increasing interest in the use of fusion protein technology for developing anti-inflammatory drugs. In comparison to single-target drugs, fusion proteins, as multiple targets drugs, have the ability to enhance the cytokine therapeutic index, resulting in improved efficacy over classical drugs. The strategy of preparing ILs or their receptors as fusion proteins is increasingly used in the treatment of autoimmune and chronic inflammation. This review focuses on the efficacy of several fusion protein drugs developed with ILs or their receptors in the treatment of autoinflammatory diseases, in order to illustrate the prospects of this new technology as an anti-inflammatory drug development protocol in the future.