Interaction between the pro-inflammatory cytokine interleukin-23 (IL-23) and IL-23 receptor (IL-23R) is related to the development of inflammatory autoimmune diseases such as psoriasis, inflammatory bowel disease, and Crohn's disease. In this study, we conducted systematic evolution of ligands by exponential enrichment (SELEX) for in vitro selection against human IL-23 and observed RNA sequence enrichment in the final SELEX round. IL-23-pull-down assay by chemiluminescence detection and fluorescence imaging demonstrated that SELEX-enriched RNA clone bound to IL-23. Quantitative polymerase chain reaction-based pull-down assay using the IL-23 alpha (IL-23A) subunit, a component of the IL-23 heterodimer, indicated that the RNA clone bound to IL-23A, which is favorable for autoimmune disease treatment. We also observed that the novel IL-23-binding RNA aptamer inhibited interaction between IL-23 and IL-23R. Thus, the novel IL-23-binding RNA aptamer can be used for IL-23 studies and has potential to be used for IL-23 diagnosis and IL-23-related inflammatory autoimmune disease treatment.

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.

Current treatments of polymyositis and dermatomyositis (PM/DM) depend on non-specific immunosuppressants. This study was performed to elucidate the role of interleukin (IL)-23, as their possible therapeutic target. As was reported earlier in PM/DM patients, serum IL-23 levels were elevated in mice with C protein induced-myositis (CIM), a murine model of PM. IL-23 was expressed by macrophages in the PM/DM and CIM muscles and by dendritic cells and macrophages in the lymph nodes from the CIM mice. It was also expressed by macrophages in the chemically injured muscles, but not those recruited into the muscles by footpad injection of Freund's complete adjuvant, demonstrating that IL-23 production should be associated with muscle damage. Genetic deletion of IL-23 as well as preventive and therapeutic administration of blocking antibodies against IL-23p19 subunit suppressed CIM. When lymph node cells from the CIM mice were transferred adoptively into naive wild type or IL-23p19 deficient recipient mice, both recipients developed myositis equally. Thus, elevated IL-23 should promote dendritic cells and macrophages to activate the autoaggressive T cells. Our findings suggest that IL-23 should mediate positive feedback loop from the muscle damage to the T cell activation and be a promising therapeutic target for autoimmune myositis.

Psoriasis is a chronic inflammatory skin disorder that affects approximately 2-3% of the population worldwide and has severe effects on patients' physical and psychological well-being. The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin (IL)-12/23p40 subunit shared by IL-12 and IL-23. Evidence suggests that specific inhibition of IL-23 would result in improvement in psoriasis. Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that specific targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg kg(-1) groups by day 196. In part 2, 10 out of 15 subjects in the 3 mg kg(-1) group and 13 out of 14 subjects in the 10 mg kg(-1) group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate-to-severe psoriasis patients as demonstrated by improvements in PASI scores and histological samples.

Neuronal cell death, amyloid β plaque formation and development of neurofibrillary tangles are among the characteristics of Alzheimer's disease (AD). In addition to neurodegeneration, inflammatory processes such as activation of microglia and astrocytes are crucial in the pathogenesis and progression of AD. Cytokines are essential immune mediators of the immune response in AD. Recent data suggest a role of interleukin 23 (IL-23) and its p40 subunit in the pathogenesis of AD and corresponding animal models, in particular concerning microglia activation and amyloid β plaque formation. Moreover, in animal models, the injection of anti-p40 antibodies resulted in reduced amyloid β plaque formation and improved cognitive performance. Here, we discuss the pathomechanism of IL-23 mediated inflammation and its role in AD.

The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbours specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17-producing γδ T (γδT17) cells, the aberrant activation of which by IL-23 can provoke psoriasis-like inflammation. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibres. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear. We exposed the skin of mice to imiquimod, which induces IL-23-dependent psoriasis-like inflammation. Here we show that a subset of sensory neurons expressing the ion channels TRPV1 and Nav1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors, DDCs failed to produce IL-23 in imiquimod-exposed skin. Consequently, the local production of IL-23-dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response. These findings indicate that TRPV1(+)Nav1.8(+) nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.

Interleukin 23 (IL-23) is a pro-inflammatory cytokine that plays an important role in inflammatory disease and tumor microenvironment. The IL-23 receptor is expressed in colon, lung, and oral carcinomas. We performed this study to investigate whether IL-23 promotes directly carcinoma cell migration and invasion as well as further explore its mechanism.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract involving aberrant activation of innate and adaptive immune responses. We have used two complementary models of IBD to examine the roles of interleukin (IL)-12 family cytokines in bacterially induced intestinal inflammation. Our results clearly show that IL-23, but not IL-12, is essential for the induction of chronic intestinal inflammation mediated by innate or adaptive immune mechanisms. Depletion of IL-23 was associated with decreased proinflammatory responses in the intestine but had little impact on systemic T cell inflammatory responses. These results newly identify IL-23 as a driver of innate immune pathology in the intestine and suggest that selective targeting of IL-23 represents an attractive therapeutic approach in human IBD.

The functionality of most secreted proteins depends on their assembly into a defined quaternary structure. Despite this, it remains unclear how cells discriminate unassembled proteins en route to the native state from misfolded ones that need to be degraded. Here we show how chaperones can regulate and control assembly of heterodimeric proteins, using interleukin 23 (IL-23) as a model. We find that the IL-23 α-subunit remains partially unstructured until assembly with its β-subunit occurs and identify a major site of incomplete folding. Incomplete folding is recognized by different chaperones along the secretory pathway, realizing reliable assembly control by sequential checkpoints. Structural optimization of the chaperone recognition site allows it to bypass quality control checkpoints and provides a secretion-competent IL-23α subunit, which can still form functional heterodimeric IL-23. Thus, locally-restricted incomplete folding within single-domain proteins can be used to regulate and control their assembly.

Studies have indicated that interleukin 23 (IL-23) plays an important role in many inflammatory- and autoimmune-related diseases. However, there is little knowledge about IL-23 in lumbar disc herniation (LDH). Thus, in this study, we aimed to find out whether IL-23 is expressed in intervertebral discs (IVDs) and what roles it may play.

Acetylcholine receptor (AChR) myasthenia gravis (MG) is a chronic autoimmune disease characterized by muscle weakness. The AChR+ autoantibodies are produced by B-cells located in thymic ectopic germinal centers (eGC). No therapeutic approach is curative. The inflammatory IL-23/Th17 pathway is activated in the thymus as well as in the blood and the muscle, contributing to the MG pathogenic events. We aimed to study a potential new therapeutic approach that targets IL-23p19 (IL-23) in the two complementary preclinical MG models: the classical experimental MG mouse model (EAMG) based on active immunization and the humanized mouse model featuring human MG thymuses engrafted in NSG mice (NSG-MG). In both preclinical models, the anti-IL-23 treatment ameliorated MG clinical symptoms. In the EAMG, the treatment reduced IL-17 related inflammation, anti-AChR IgG2b antibody production, activated transduction pathway involved in muscle regeneration and ameliorated the signal transduction at the neuromuscular junction. In the NSG-MG model, the treatment reduced pathogenic Th17 cell population and expression of genes involved in eGC stabilization and B-cell development in human MG thymus biopsies. Altogether, these data suggest that a therapy targeting IL-23p19 may promote significant clinical ameliorations in AChR+ MG disease due to concomitant beneficial effects on the thymus and skeletal muscle defects.

Although commensal flora is involved in the regulation of immunity, the interplay between cytokine signaling and microbiota in atherosclerosis remains unknown. We found that interleukin (IL)-23 and its downstream target IL-22 restricted atherosclerosis by repressing pro-atherogenic microbiota. Inactivation of IL-23-IL-22 signaling led to deterioration of the intestinal barrier, dysbiosis, and expansion of pathogenic bacteria with distinct biosynthetic and metabolic properties, causing systemic increase in pro-atherogenic metabolites such as lipopolysaccharide (LPS) and trimethylamine N-oxide (TMAO). Augmented disease in the absence of the IL-23-IL-22 pathway was mediated in part by pro-atherogenic osteopontin, controlled by microbial metabolites. Microbiota transfer from IL-23-deficient mice accelerated atherosclerosis, whereas microbial depletion or IL-22 supplementation reduced inflammation and ameliorated disease. Our work uncovers the IL-23-IL-22 signaling as a regulator of atherosclerosis that restrains expansion of pro-atherogenic microbiota and argues for informed use of cytokine blockers to avoid cardiovascular side effects driven by microbiota and inflammation.

IL-23R gene polymorphisms and the association of these polymorphisms with serum IL-23 levels were investigated in patients with psoriasis in the current study.

Periapical lesions are characterized by the destruction of periapical bone, and occur as a result of local inflammatory responses to root canal infection by microorganisms including Porphyromonas endodontalis (P. endodontalis). P. endodontalis and its primary virulence factor, lipopolysaccharide (LPS), are associated with the development of periapical lesions and alveolar bone loss. Interleukin‑23 (IL‑23) is critical in the initiation and progression of periodontal disease via effects on peripheral bone metabolism. The present study investigated the expression of IL‑23 in tissue where a periapical lesion was present, and the effect of P. endodontalis LPS on the expression of IL‑23 in periodontal ligament (PDL) cells. Reverse transcription‑ quantitative polymerase chain reaction and immunohistochemistry revealed increased levels of IL‑23 expression in tissue with periapical lesions compared with healthy PDL tissue. Treatment with P. endodontalis LPS increased the expression of IL‑23 in the SH‑9 human PDL cell line. BAY11‑7082, a nuclear factor κB inhibitor, suppressed P. endodontalis LPS‑induced IL‑23 expression in SH‑9 cells. Treatment of RAW264.7 cells with conditioned medium from P. endodontalis LPS‑treated SH‑9 cells promoted osteoclastogenesis. By contrast, RAW264.7 cells treated with conditioned medium from IL‑23‑knockdown SH‑9 cells underwent reduced levels of osteoclastogenesis. The results of the present study indicated that the expression of IL‑23 in PDL cells induced by P. endodontalis LPS treatment may be involved in the progression of periapical lesions via stimulation of the osteoclastogenesis process.

NLRP3 inflammasome has been reported associated with some inflammatory and autoimmune diseases. We previously researches showed that interleukin-23 (IL-23) and interleukin-17 (IL-17) aggravates the ischaemic injury of the brain tissue. However, it is poorly understood whether the NLPR3 inflammasome was involved in regulating and activating the IL-23/IL-17 axis in ischaemic stroke. We aimed to delineate whether the NLRP3 inflammasome signalling provokes the IL-23/IL-17 axis and interleukin-23 receptor (IL-23R) inducing the ischaemia-reperfusion injury of the brain in mice.

The interleukin (IL)-12-type cytokines IL-12 and IL-23 are involved in T-helper (Th) 1 and Th17 immunity, respectively. They share the IL-12 receptor β1 (IL-12Rβ1) as one component of their receptor signaling complexes, with IL-12Rβ2 as second receptor for IL-12 and IL-23R for IL-23 signal transduction. Stimulation with IL-12 and IL-23 results in activation of receptor-associated Janus kinases (Jak) and phosphorylation of STAT proteins in target cells. The Janus kinase tyrosine kinase (Tyk) 2 associates with IL-12Rβ1, whereas Jak2 binds to IL-23R and also to IL-12Rβ2. Receptor association of Jak2 is mediated by Box1 and Box2 motifs located within the intracellular domain of the receptor chains. Here we define the Box1 and Box2 motifs in IL-12Rβ1 and an unusual Jak2-binding site in IL-23R by the use of deletion and site-directed mutagenesis. Our data show that nonfunctional box motifs abolish IL-12- and IL-23-induced STAT3 phosphorylation and cytokine-dependent proliferation of Ba/F3 cells. Coimmunoprecipitation of Tyk2 by IL-12Rβ1 and Jak2 by IL‑23R supported these findings. In addition, our data demonstrate that association of Jak2 with IL-23R is mandatory for IL-12 and/or IL-23 signaling, whereas Tyk2 seems to be dispensable.

The aim of the study was to evaluate the role of Interleukin-17 (IL-17), Interleukin-23 (IL-23), and transforming growth factor-β (TGF-β) in pregnancy complicated by placental insufficiency and in normal pregnancy.

Interleukin-23/interleukin-23 receptor (IL-23/IL-23R) has been implicated in many inflammatory diseases. Previous research mainly focused on its ability to induce IL-17 production from T cells. However, few studies have investigated its role in cerebral ischemic injury. The aim of our study was to explore the potential effect of IL-23 on cells of the neurovascular unit (NVU) under an oxygen-glucose deprivation (OGD) condition and the role of IL-23R in IL-23-mediated effect. OGD of primary cells of the NVU and permanent middle cerebral artery occlusion (pMCAO) were used to produce experimental stroke in vitro and in vivo, respectively. IL-23 and IL-23R were detected by immunohistochemistry and western blot in pMCAO mice. Metabolic viability of cultured cells was assessed by MTT assay. The cell-associated proteins (Bcl-2, AQP4 and ET-1) were determined by western blot and enzyme-linked immunosorbent assay (ELISA). Immunofluorescence staining and western blot were used to detect the IL-23R expression. The results showed that the expression of IL-23/IL-23R was elevated in pMCAO mice. IL-23 could aggravate neuron damage, astrocyte swelling, and further impair the integrity of blood-brain barrier induced by OGD. In addition, the effect of IL-23 on cells of the NVU is mediated by IL-23R and is likely IL-23R-expression-level dependent. However, there are no such biological properties for the IL-23p19 subunit alone. Our study provides the first evidence that IL-23 has a toxic effect on cells of the NVU under OGD stress, which is mediated by IL-23R. These results not only help us better understand the role of IL-23/IL-23R in brain ischemia, but also provide a potential therapeutic target in stroke.

Interleukin (IL) 12 and IL23 are two related heterodimeric cytokines produced by antigen-presenting cells. The balance between these two cytokines plays a crucial role in the control of Th1/Th17 responses and autoimmune inflammation. Most studies focused on their transcriptional regulation. Herein, we explored the role of the adenine and uridine-rich element (ARE)-binding protein tristetraprolin (TTP) in influencing mRNA stability of IL12p35, IL12/23p40, and IL23p19 subunits. LPS-stimulated bone marrow-derived dendritic cells (BMDCs) from TTP(-/-) mice produced normal levels of IL12/23p40. Production of IL12p70 was modestly increased in these conditions. In contrast, we observed a strong impact of TTP on IL23 production and IL23p19 mRNA stability through several AREs in the 3' untranslated region. TTP(-/-) mice spontaneously develop an inflammatory syndrome characterized by cachexia, myeloid hyperplasia, dermatitis, and erosive arthritis. We observed IL23p19 expression within skin lesions associated with exacerbated IL17A and IL22 production by infiltrating γδ T cells and draining lymph node CD4 T cells. We demonstrate that the clinical and immunological parameters associated with TTP deficiency were completely dependent on the IL23-IL17A axis. We conclude that tight control of IL23 mRNA stability by TTP is critical to avoid severe inflammation.

Variants of the gene coding for interleukin 23 receptor (IL23R) have been confirmed to be associated with inflammatory bowel disease (IBD). Based on similarities in the autoimmune features of IBD and multiple sclerosis (MS), we selected this gene for analysis as a candidate gene in MS. We tested 32 single nucleotide polymorphisms tagging all parts of the gene including 10 markers previously studied in IBD for association with MS. The study population consisted of 1114 MS patients and 1235 controls of Scandinavian origin. None of the tests showed more than very modest differences between patients and controls. Haplotypes were constructed and were also similarly distributed in patients and controls. We conclude that it is unlikely that the IL23R gene confers any significant risk for MS.