Assessment of interleukin 17A and 23 in the course of bladder cancer and selected benign urological diseases.

Several cytokines have been indicated to be significantly involved in urological diseases. Interleukin 17A (IL-17A) and interleukin 23 (IL-23) have recently received attention for their involvement in inflammatory diseases and cancers. The aim of the study was to show changes in the level of pro-inflammatory interleukins IL-17A and IL-23 in patients with bladder cancer (BC) and selected urological diseases. An important cognitive aspect was to study the interdependencies between the studied interleukins and to assess their diagnostic value for such diseases. The material for the study was urine sample from patients with BC, urinary tract infection (UTI), urolithiasis, benign prostatic hyperplasia (BPH), US (urethral stricture), which was compared to the urine sample of healthy people without urological disorders. Interleukin concentrations were measured by the immunoenzymatic method. The levels of IL-17A and IL-23 in the urine of patients with BC, UTI, BPH and US were significantly higher compared to the control group. Statistically significant differences were found in the level of both interleukins compared to the control group in all diseases except urolithiasis. IL-17A and IL-23 correlated with each other in patients with all urological diseases except urolithiasis. The results of the conducted studies showed that selected urological diseases changed the levels of IL-17A and IL-23 in the urine of patients. The observations made confirmed the participation of these interleukins in the course of the urological diseases, especially in BC, and allowed to classify them as potentially useful parameters for diagnostic purposes.

Gums make IL-23, no professionals needed.

IL-23 activates pathogenic Th17 cells to drive inflammatory disease at barrier surfaces. Kim et al. now identify oral epithelial cells as the critical producers of IL-23 in human and mouse periodontitis, linking microbial dysbiosis to non-hematopoietic regulation of IL-17-associated inflammation.

Interleukin inhibitors and the associated risk of candidiasis.

Interleukins (ILs) are vital in regulating the immune system, enabling to combat fungal diseases like candidiasis effectively. Their inhibition may cause enhanced susceptibility to infection. IL inhibitors have been employed to control autoimmune diseases and inhibitors of IL-17 and IL-23, for example, have been associated with an elevated risk of Candida infection. Thus, applying IL inhibitors might impact an individual's susceptibility to Candida infections. Variations in the severity of Candida infections have been observed between individuals with different IL inhibitors, necessitating careful consideration of their specific risk profiles. IL-1 inhibitors (anakinra, canakinumab, and rilonacept), IL-2 inhibitors (daclizumab, and basiliximab), and IL-4 inhibitors (dupilumab) have rarely been associated with Candida infection. In contrast, tocilizumab, an inhibitor of IL-6, has demonstrated an elevated risk in the context of coronavirus disease 2019 (COVID-19) treatment, as evidenced by a 6.9% prevalence of candidemia among patients using the drug. Furthermore, the incidence of Candida infections appeared to be higher in patients exposed to IL-17 inhibitors than in those exposed to IL-23 inhibitors. Therefore, healthcare practitioners must maintain awareness of the risk of candidiasis associated with using of IL inhibitors before prescribing them. Future prospective studies need to exhaustively investigate candidiasis and its associated risk factors in patients receiving IL inhibitors. Implementing enduring surveillance methods is crucial to ensure IL inhibitors safe and efficient utilization of in clinical settings.

Expanding the Psoriasis Framework: Immunopathogenesis and Treatment Updates.

Psoriasis is a chronic heterogeneous condition with multiple available treatment options that have resulted in dramatic disease improvements for patients. IL-23/IL-17 signaling is the central immune signaling pathway driving psoriasis, though recent research has uncovered other key contributing signals such as IL-17C, IL-17F, IL-36, and tyrosine kinase 2 (TYK2). Novel therapeutic targets inhibiting these cytokines have expanded our understanding of the pathogenesis of psoriasis. IL-23/IL-17 signaling is critical for the development of epidermal hyperplasia and the mature psoriatic plaque in susceptible individuals. Increased IL-17 and IL-23 expression works synergistically with other cytokines, such as IL-12, IL-22, IL-36, tumor necrosis factor (TNF), and interferon (IFN), to help create a self-sustaining, feed-forward circuit in keratinocytes, which contributes to the chronicity of the disease. This clinical review highlights recent discoveries in the immunopathogenesis of psoriasis and summarizes new antipsoriasis therapies targeting IL-36, IL-17F, aryl hydrocarbon receptors (AHRs), phosphodiesterase 4 (PDE4), and TYK2 signaling. Despite recent success in the treatment of psoriasis, continued research is needed to further advance disease understanding and shape management strategies.

Interleukin-23 levels in umbilical cord blood are associated with neurodevelopmental trajectories in infancy.

Our previous study, which aimed to understand the early neurodevelopmental trajectories of children with and without neurodevelopmental disorders, identified five classes of early neurodevelopmental trajectories, categorized as high normal, normal, low normal, delayed, and markedly delayed. This investigation involved measurement using the Mullen Scale of Early Learning in a representative sample of Japanese infants followed up from the age of 0 to 2 years (Nishimura et al., 2016). In the present study, we investigated the potential association between cytokine concentrations in umbilical cord serum with any of the five classes of neurodevelopmental trajectories previously assigned, as follows: high normal (N = 85, 13.0%), normal (N = 322, 49.1%), low normal (N = 137, 20.9%), delayed (N = 87, 13.3%), and markedly delayed (N = 25, 3.8%) in infancy. Decreased interleukin (IL)-23 levels in the cord blood were associated with the markedly delayed class, independent of potential confounders (odds ratio, 0.44; 95%confidence interval: 0.26-0.73). Furthermore, IL-23 levels decreased as the developmental trajectory became more delayed, demonstrating that IL-23 plays an important role in development, and is useful for predicting the developmental trajectory at birth.

Anti-Interleukin-23 Autoantibodies in Adult-Onset Immunodeficiency.

BACKGROUND: Autoantibodies against interleukin-12 (anti-interleukin-12) are often identified in patients with thymoma, but opportunistic infections develop in only some of these patients. Interleukin-12 (with subunits p40 and p35) shares a common subunit with interleukin-23 (subunits p40 and p19). In a patient with disseminated Burkholderia gladioli infection, the identification of both anti-interleukin-23 and anti-interleukin-12 prompted further investigation. METHODS: Among the patients (most of whom had thymoma) who were known to have anti-interleukin-12, we screened for autoantibodies against interleukin-23 (anti-interleukin-23). To validate the potential role of anti-interleukin-23 with respect to opportunistic infection, we tested a second cohort of patients with thymoma as well as patients without either thymoma or known anti-interleukin-12 who had unusual infections. RESULTS: Among 30 patients with anti-interleukin-12 who had severe mycobacterial, bacterial, or fungal infections, 15 (50%) also had autoantibodies that neutralized interleukin-23. The potency of such neutralization was correlated with the severity of these infections. The neutralizing activity of anti-interleukin-12 alone was not associated with infection. In the validation cohort of 91 patients with thymoma, the presence of anti-interleukin-23 was associated with infection status in 74 patients (81%). Overall, neutralizing anti-interleukin-23 was detected in 30 of 116 patients (26%) with thymoma and in 30 of 36 patients (83%) with disseminated, cerebral, or pulmonary infections. Anti-interleukin-23 was present in 6 of 32 patients (19%) with severe intracellular infections and in 2 of 16 patients (12%) with unusual intracranial infections, including Cladophialophora bantiana and Mycobacterium avium complex. CONCLUSIONS: Among patients with a variety of mycobacterial, bacterial, or fungal infections, the presence of neutralizing anti-interleukin-23 was associated with severe, persistent opportunistic infections. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Interleukin-12: Structure, Function, and Its Impact in Colorectal Cancer.

Interleukin 12 (IL-12) is a heterodimer consisting of 2 subunits, p35 and p40, with unique associations and interacting functions with its family members. IL-12 is one of the most important cytokines regulating the immune system response and is integral to adaptive immunity. IL-12 has shown marked therapeutic potential in a variety of tumor types. This review therefore summarizes the characteristics of IL-12 and its application in tumor treatment, focusing on its antitumor effects in colorectal cancer (CRC) and potential radiosensitization mechanisms. We aim to provide a current reference for IL-12 and other potential CRC treatment strategies.

Research progress of Ustekinumab in the treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic, recurrent gastrointestinal disorder with elusive etiology. Interleukin-12 (IL-12) and IL-23 have emerged as key proinflammatory mediators/cytokines in IBD pathogenesis. Ustekinumab (UST), targeting IL-12 and IL-23, has demonstrated promising efficacy and safety in the treatment of IBD. Recently, UST has become increasingly favored as a potential first-line treatment option. This review delineates UST's mechanism of action, its clinical applications in IBD, including the response rates, strategies for dose optimization for case of partial or lost response, and potential adverse events. This review aims to offer a comprehensive understanding of UST's role as a therapeutic option in IBD management.

miRNA­21 promotes the progression of acute liver failure via the KLF6/autophagy/IL­23 signaling pathway.

Acute liver failure (ALF) is a complex syndrome characterized by overactivation of innate immunity, and the recruitment and differentiation of immune cells at inflammatory sites. The present study aimed to explore the role of microRNA (miRNA/miR)­21 and its potential mechanisms underlying inflammatory responses in ALF. Baseline serum miR­21 was analyzed in patients with ALF and healthy controls. In addition, miR­21 antagomir was injected via the tail vein into C57BL/6 mice, and lipopolysaccharide/D­galactosamine (LPS/GalN) was injected into mice after 48 h. The expression levels of miR­21, Krüppel­like­factor­6 (KLF6), autophagy­related proteins and interleukin (IL)­23, and hepatic pathology were then assessed in the liver tissue. Furthermore, THP­1­derived macrophages were transfected with a miRNA negative control, miR­21 inhibitor, miR­21 mimics or KLF6 overexpression plasmid, followed by treatment with or without rapamycin, and the expression levels of miR­21, KLF6, autophagy­related proteins and IL­23 were evaluated. The results revealed that baseline serum miR­21 levels were significantly upregulated in patients with ALF. In addition, LPS/GalN­induced ALF was attenuated in the antagomir­21 mouse group. KLF6 was identified as a target of miR­21­5p with one putative seed match site identified by TargetScan. A subsequent luciferase activity assay demonstrated a direct interaction between miR­21­5p and the 3'­UTR of KLF6 mRNA. Further experiments suggested that miR­21 promoted the expression of IL­23 via inhibiting KLF6, which regulated autophagy. In conclusion, in the present study, baseline serum miR­21 levels were highly upregulated in patients with ALF, antagomir­21 attenuated LPS/GalN­induced ALF in a mouse model, and miR­21 could promote the expression of IL­23 via inhibiting KLF6.

Sex differences in cytokines and adipokines in obese patients with PsA and controls undergoing a weight loss intervention.

OBJECTIVE: In this post hoc analysis of a previously published study, we compared cytokines and adipokine levels in women and men with psoriatic arthritis (PsA) at baseline (BL) and 6 months (M6) following a weight loss intervention. METHODS: Patients with PsA (n=41) between 25 and 75 years of age, with body mass index (BMI)≥33 kg/m2 were included in a weight loss intervention with a very low energy diet (VLED) for 12 or 16 weeks depending on BL BMI<40 or ≥40 kg/m2. As controls (n=39), obese individuals, already planned for VLED treatment were recruited and matched for sex, age and weight to the patients with PsA. Cytokines and adipokines were measured at BL and M6. RESULTS: At BL, serum levels of interleukin (IL)-23, leptin and high molecular weight-adiponectin were higher in women with PsA compared with men, whereas serum levels of interferon (IFN)-γ, IL-12/IL-23 p40 and IL-13 were significantly lower in women. Serum IL-23 was significantly reduced at M6 compared with BL in women but not in men with PsA. In women with PsA, the reduction in IL-23 at M6, ∆IL-23, were positively correlated with ∆Disease Activity Score 28 C reactive protein (CRP) (Spearman's correlation (rS)=0.486, p=0.016), ∆CRP (rS=0.468, p=0.021), ∆leptin (rS=0.683, p<0.001) and negatively correlated with ∆total-adiponectin (rS=-0.433, p=0.035). Also in women, ∆Disease Activity in Psoriatic Arthritis was positively correlated with ∆tumour necrosis factor-α (rS=0.417, p=0.034), ∆IL-1ß (rS=0.550, p=0.034), ∆IFN-γ (rS=0.414, p=0.035) and ∆leptin (rS=0.410, p=0.038). None of these correlations were significant in men with PsA. CONCLUSIONS: Women and men with PsA differed with regard to serum levels of cytokines and adipokines before and after weight loss.

Epithelial-derived interleukin-23 promotes oral mucosal immunopathology.

At mucosal surfaces, epithelial cells provide a structural barrier and an immune defense system. However, dysregulated epithelial responses can contribute to disease states. Here, we demonstrated that epithelial cell-intrinsic production of interleukin-23 (IL-23) triggers an inflammatory loop in the prevalent oral disease periodontitis. Epithelial IL-23 expression localized to areas proximal to the disease-associated microbiome and was evident in experimental models and patients with common and genetic forms of disease. Mechanistically, flagellated microbial species of the periodontitis microbiome triggered epithelial IL-23 induction in a TLR5 receptor-dependent manner. Therefore, unlike other Th17-driven diseases, non-hematopoietic-cell-derived IL-23 served as an initiator of pathogenic inflammation in periodontitis. Beyond periodontitis, analysis of publicly available datasets revealed the expression of epithelial IL-23 in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human disease. Collectively, this work highlights an important role for the barrier epithelium in the induction of IL-23-mediated inflammation.

IL-23/IL-17 axis levels in gingival crevicular fluid of subjects with periodontal disease: a systematic review.

BACKGROUND: The IL-23/IL-17 axis plays an important role in the immunopathogenesis of periodontal disease. A systematic review was conducted to synthesize all research reporting on the levels of the IL-23/IL-17 axis in gingival crevicular fluid (GCF) from subjects with gingivits, and periodontitis, compared to healthy controls. METHODS: The protocol followed the PRISMA, and Cochrane guidelines, and was registered with the Open Science Framework (OSF): https://doi.org/10.17605/OSF.IO/7495V . A search was conducted in the electronic databases PubMed/MEDLINE, Scopus, Google Schoolar, and Cochrane from November 15th, 2005, to May 10th, 2023. The quality of the studies was assessed using the JBI tool for cross-sectional studies. RESULTS: The search strategy provided a total of 2,098 articles, of which 12 investigations met the inclusion criteria. The total number of patients studied was 537, of which 337 represented the case group (subjects with gingivitis, and chronic periodontitis), and 200 represented the control group (periodontally healthy subjects). The ages of the patients ranged from 20 to 50 years, with a mean (SD) of 36,6 ± 4,2, of which 47% were men, and 53% were women. 75% of the investigations collected GCF samples with absorbent paper strips, and analyzed cytokine IL-17 levels individually. In addition, qualitative analysis revealed that there are differences between IL-23/IL-17 axis levels in subjects with chronic periodontitis, gingivitis and healthy controls. CONCLUSIONS: Thus, IL-23/IL-17 axis levels could be used in the future as a diagnostic tool to distinguish between periodontal diseases.

Identification of the grass carp interleukin-23 receptor and its proinflammatory role in intestinal inflammation.

The interleukin 23 receptor (IL-23R) is associated with a variety of inflammatory diseases in humans and other mammals. However, whether IL-23R is involved in inflammatory diseases in teleost fish is less understood. Thus, to investigate the potential involvement of IL-23R in fish inflammatory diseases, the full-length cDNA of IL-23R from grass carp Ctenopharyngodon idella was cloned and used to generate a recombinant protein (rgcIL-23R) containing the extracellular domain of IL-23R, against which a polyclonal antibody (rgcIL-23R pAb) was then developed. qPCR analysis revealed that IL-23R mRNA was significantly upregulated in most grass carp tissues in response to infection with Gram-negative Aeromonas hydrophila. Treatment with rgcIL-23R significantly induced IL-17A/F1 expression in C. idella kidney (CIK) cells. By contrast, knockdown of IL-23R caused significant decreases in IL-23R, STAT3, and IL-17N expression in CIK cells after lipopolysaccharide (LPS) stimulation. Similarly, rgcIL-23R pAb treatment effectively inhibited the LPS-induced increase in the expression of IL-23 subunit genes and those of the IL-23/IL-17 pathway in CIK cells. Furthermore, intestinal symptoms identical to those caused by A. hydrophila were induced by anal intubation with rgcIL-23R, but suppressed by rgcIL-23R pAb. Therefore, these results suggest that IL-23R has a crucial role in the regulation of intestinal inflammation and, thus, is a promising target for controlling inflammatory diseases in farmed fish.

The Dysregulated IL-23/TH17 Axis in Endometriosis Pathophysiology.

Endometriosis is a chronic inflammatory disease in which endometrial-like tissue grows ectopically, resulting in pelvic pain and infertility. IL-23 is a key contributor in the development and differentiation of TH17 cells, driving TH17 cells toward a pathogenic profile. In a variety of inflammatory and autoimmune disorders, TH17 cells secrete proinflammatory cytokines, including IL-17, contributing to disease pathophysiology. Our studies and others have implicated IL-17 and TH17 cell dysregulation in endometriosis, which is associated with disease severity. In this article, we address whether IL-23-driven TH17 cells contribute to cardinal features of lesion proliferation, vascularization, and inflammation in endometriosis using patient samples, representative cell lines, and our established mouse model of endometriosis. The results indicated dysregulated expression of key genes in the IL-23/TH17 axis in patient ectopic and eutopic endometrial samples and increased IL-23 protein in patient plasma compared with controls. In vitro studies using primary human TH cells determined that rIL-23 mixture treatment increased pathogenic TH17 cell frequency. Similarly, rIL-23 treatment of cell lines (12Z cells, EECCs, HUVECs, and hESCs) representative of the endometriotic lesion microenvironment increased cytokines and growth factors, which play a role in lesion establishment and maintenance. In a syngeneic mouse model of endometriosis, rIL-23 treatment altered numbers of myeloid and T cell subsets in peritoneal fluid and increased giant cells within the lesion. Lesions from rIL-23-treated mice did not reveal significant alterations in proliferation/vascularization, although trends of increased proliferation and vascularization were observed. Collectively, these findings provide insights into the impact of the IL-23/TH17 axis on local immune dysfunction and broadly on endometriosis pathophysiology.

Risankizumab, a therapeutic alternative for psoriasis in people living with HIV.

The management of psoriasis in individuals with human immunodeficiency virus (HIV) presents a unique challenge, marked by a more severe progression and limited efficacy of first- and second-line treatments. Although conventional systemic therapies might be considered, these agents are immunosuppressants, making their use challenging in people living with HIV (PLHIV). Biologic agents are frequently used in individuals with moderate-to-severe psoriasis, but their efficacy and safety data in PLHIV are very limited, as this patient group tends to be excluded from clinical trials. Risankizumab is a selective interleukin-23 (IL-23) inhibitor that has demonstrated a favourable safety profile and high efficacy in long-term studies and clinical practice. This current case report presents two clinical cases of PLHIV with plaque psoriasis who were effectively treated with the biologic agent risankizumab, with no reported safety issues. Although there are limited data on the use of biologics in PLHIV, this case series suggests that IL-23 inhibitors, namely risankizumab, might be a valuable therapeutic option for this population. Additional research and larger studies are needed to gain a more comprehensive understanding of the long-term safety and efficacy of IL-23 inhibitors in individuals affected by HIV.

Yinxieling decoction ameliorates psoriasis by regulating the differentiation and functions of Langerhans cells via the TGF-ß1/PU.1/IL-23 signal axis.

Langerhans cells (LCs) play a critical role in skin immune responses and the development of psoriasis. Yinxieling (YXL) is a representative Chinese herbal medicine for the treatment of psoriasis in South China. It was found to improve psoriasis without obvious side effects in the clinic. Here we attempted to clarify whether and how YXL regulates the differentiation and functions of LCs in Imiquimod (IMQ)-induced psoriasis in vivo and induced LCs in vitro. The Psoriasis Area Severity Index (PASI) score was used to evaluate the efficacy of YXL for IMQ-induced psoriasis-like mice. Flow cytometry was utilized to analyze the effects of YXL, to regulate the differentiation, migration, maturation, and antigen presentation of LCs. The results show that YXL significantly alleviated skin inflammation, as reduced in PASI score and classic psoriasis characteristics in pathological sections. Although there was no effect on the proportion of total DCs in the skin-draining lymph nodes, the expression of epidermal LCs and its transcription factor PU.1 were both markedly inhibited. LCs were also prevented from migrating from epidermal to skin-draining lymph nodes and mature. In addition, the number of LCs carrying antigens in the epidermis increased, which suggested that YXL could effectively prevent LCs from presenting antigens. In vitro, YXL had a significant impact on inhibiting the differentiation of LCs. Further data showed that YXL decreased the relative expression of transforming growth factor-ß (TGFß) messenger RNA (mRNA) and interleukin-23 (IL-23) mRNAs. Thus, YXL alleviates psoriasis by regulating differentiation, migration, maturation, and antigen presentation via the TGFß/PU.1/IL-23 signal axis.

Study of IL-17 and Intercellular Adhesion Molecule-1 in Conjunctivochalasis Using Correlation Analysis.

PURPOSE: The aim of this study was to observe the expression of interleukin (IL)-17 and intercellular adhesion molecule (ICAM)-1 in conjunctivochalasis (CCH) and to analyze the correlations between cytokines and the severity of CCH. METHODS: Serum samples were collected from 22 patients with CCH and 18 normal controls (NCs). The Ocular Surface Disease Index, tear film break-up time, Schirmer I test, and corneal fluorescein staining were used to evaluate the ocular surface signs and symptoms. The concentrations of IL-17, IL-23, and ICAM-1 in serum and cellular supernatants were measured by enzyme-linked immunosorbent assays, and the gene expression levels of cytokines were measured by a quantitative real-time polymerase chain reaction. The relationships between serum concentrations of IL-17, IL-23, and ICAM-1 with clinical ocular surface parameters in CCH were analyzed using the Spearman correlation analysis. RESULTS: The concentrations of IL-17 and ICAM-1 in serum and cellular supernatants of CCH were significantly higher than those of NCs (all P < 0.001). The concentrations of IL-23 in serum and cellular supernatants of CCH showed no significant difference from those of NCs ( P > 0.05). The mRNA expression levels of IL-17 and ICAM-1 in conjunctival fibroblasts of CCH were significantly higher than those of NCs (all P < 0.001). The mRNA expression of IL-23 in conjunctival fibroblasts of CCH was higher than that of NCs, without a significant difference ( P > 0.05). Furthermore, the serum concentrations of IL-17 and ICAM-1 were positively correlated with Ocular Surface Disease Index and fluorescein staining (all P < 0.05), and negatively correlated with break-up time and Schirmer I test of CCH (all P < 0.05). CONCLUSIONS: The expression levels of IL-17 and ICAM-1 were significantly increased in CCH serum and associated with the disease severity. We postulate that IL-17 and ICAM-1 may play a role in the pathogenesis of CCH. IL-17 and ICAM-1 antagonists may be a potential treatment option for CCH in the future.