更新于：2024-04-01
IL-23p19
白细胞介素-23亚单位p19
更新于：2024-04-01
基本信息
别名 IL-23、IL-23 subunit alpha、IL-23-A + [11] |
简介 Associates with IL12B to form the pro-inflammatory cytokine IL-23 that plays different roles in innate and adaptive immunity (PubMed:11114383). Released by antigen-presenting cells such as dendritic cells or macrophages, binds to a heterodimeric receptor complex composed of IL12RB1 and IL23R to activate JAK2 and TYK2 which then phosphorylate the receptor to form a docking site leading to the phosphorylation of STAT3 and STAT4 (PubMed:32474165, PubMed:29287995, PubMed:33606986). This process leads to activation of several pathways including p38 MAPK or NF-kappa-B and promotes the production of pro-inflammatory cytokines such as interleukin-17A/IL17A (PubMed:12023369). In turn, participates in the early and effective intracellular bacterial clearance (PubMed:32474165). Promotes the expansion and survival of T-helper 17 cells, a CD4-positive helper T-cell subset that produces IL-17, as well as other IL-17-producing cells (PubMed:17676044). |
关联
靶点 |
作用机制 |
在研机构 |
原研机构 |
在研适应症 |
非在研适应症 |
最高研发阶段 |
首次获批国家/地区 |
首次获批日期 |
靶点 |
作用机制 |
在研机构 |
原研机构 |
在研适应症 |
非在研适应症 |
最高研发阶段 |
首次获批国家/地区 |
首次获批日期 |
靶点 |
作用机制 |
在研机构 |
原研机构 |
在研适应症 |
非在研适应症 |
最高研发阶段 |
首次获批国家/地区 |
首次获批日期 |
A Phase 3, Multicenter, Randomized, Platform Study of p19 Inhibition of the IL-23 Pathway to Establish Efficacy in Pediatric Crohn's Disease
A Phase 3, Multicenter, Randomized Clinical Study to Evaluate Mirikizumab in Pediatric Crohn's Disease
Risankizumab in Children With Crohn's Disease (RisaKids): A Multi-center PORTO Group Prospective Study
100 项与 IL-23p19 相关的临床结果
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100 项与 IL-23p19 相关的转化医学
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2024-02-20Biochemical pharmacology
IL-23p19 deficiency reduces M1 macrophage polarization and improves stress-induced cardiac remodeling by alleviating macrophage ferroptosis in mice.
Article
作者: Xiyi Lu ; Qingwei Ji ; Heng Pan ; Yongqi Feng ; Di Ye ; Liren Gan ; Jun Wan ; Jing Ye
BACKGROUND:
Interleukin-23p19 (IL-23p19) has been demonstrated to be involved in the occurrence and development of cardiovascular diseases such as myocardial infarction and atherosclerosis. This study aimed to examine whether IL-23p19 regulates cardiac remodeling processes and explore its possible mechanisms.
METHODS AND RESULTS:
Transverse aortic constriction was performed to construct a mouse cardiac remodeling model, and sham surgery was used as a control. The results showed that IL-23p19 expression was increased in the heart after surgery and may be mainly produced by cardiac macrophages. Knockout of IL-23p19 attenuated M1 macrophage polarization, reduced ferroptosis, improved the process of cardiac remodeling and alleviated cardiac dysfunction in TAC mice. Cell culture experiments found that macrophages were the main cause of ferroptosis when phenylephrine (PE) was added, and blocking ferroptosis with ferrostatin-1 (Fer-1), a ferroptosis inhibitor, significantly inhibited M1 macrophage polarization. Treatment with Fer-1 also improved cardiac remodeling and alleviated cardiac dysfunction in IL-23p19-/- mice subjected to TAC surgery. Finally, TAC IL-23p19-/- mice that were administered macrophages isolated from WT mice exhibited an increased proportion of M1 macrophages and aggravated cardiac remodeling, and these effects were reversed when Fer-1 was administered.
CONCLUSION:
Knockout of IL-23p19 may attenuate M1 macrophage polarization to improve the cardiac remodeling process by reducing macrophage ferroptosis, and IL-23p19 may be a potential target for the prevention and treatment of cardiac remodeling.
2024-02-15Arthritis & rheumatology (Hoboken, N.J.)
A Novel human IL-23A Overexpressing Mouse Model of Systemic Lupus Erythematosus.
Article
作者: Eleni Christodoulou-Vafeiadou ; Christina Geka ; Lida Iliopoulou ; Lydia Ntari ; Maria C Denis ; Niki Karagianni ; George Kollias
OBJECTIVE:
Interleukin-23 (IL-23) is a crucial cytokine implicated in chronic inflammation and autoimmunity, associated with various diseases like psoriasis, psoriatic arthritis, and systemic lupus erythematosus (SLE). This study aimed to create and characterize a transgenic mouse model (TghIL23A) overexpressing human IL23A, providing a valuable tool for investigating the pathogenic role of hIL23A and evaluating the efficacy of anti-human-IL23A therapeutics.
METHODS:
TghIL23A mice were generated via microinjection of CBAxC57BL/6 zygotes with a fragment of the human IL23A gene, flanked by its 5'-regulatory sequences and the 3'UTR of human beta-globin. The TghIL23A pathology was assessed through hematological and biochemical analyses, cytokine and anti-nuclear antibody detection, histopathological examination of skin and renal tissues. The response to the anti-hIL23A therapeutic agent guselkumab, was evaluated in groups of 8 mixed-sex mice receiving subcutaneous treatment twice weekly for 10 weeks, using clinical, biomarker and histopathological readouts.
RESULTS:
TghIL23A mice exhibited interactions between hIL23A and mouse IL23/IL12p40, and developed a chronic multiorgan autoimmune disease marked by proteinuria, anti-dsDNA antibodies, severe inflammatory lesions in the skin, and milder phenotypes in the kidneys and lungs. The TghIL23A pathological features exhibited significant similarities to those observed in human SLE patients and they were reversed following guselkumab treatment.
CONCLUSIONS:
We have generated and characterized a novel genetic mouse model of SLE, providing proof-of-concept for the etiopathogenic role of hIL-23A. This new model has a normal lifespan and integrates several characteristics of the human disease's complexity and chronicity making it an attractive preclinical tool for studying IL23-dependent pathogenic mechanisms and assessing the efficacy of anti-hIL23A or modeled disease-related therapeutics.
2024-02-12Allergology international : official journal of the Japanese Society of Allergology
Topical application of activator protein-1 inhibitor T-5224 suppresses inflammation and improves skin barrier function in a murine atopic dermatitis-like dermatitis.
Article
作者: Minori Sasakura ; Hitoshi Urakami ; Kota Tachibana ; Kenta Ikeda ; Ken-Ichi Hasui ; Yoshihiro Matsuda ; Ko Sunagawa ; Daisuke Ennishi ; Shuta Tomida ; Shin Morizane
BACKGROUND:
Selective activator protein (AP)-1 inhibitors are potentially promising therapeutic agents for atopic dermatitis (AD) because AP-1 is an important regulator of skin inflammation. However, few studies have investigated the effect of topical application of AP-1 inhibitors in treating inflammatory skin disorders.
METHODS:
Immunohistochemistry was conducted to detect phosphorylated AP-1/c-Jun expression of skin lesions in AD patients. In the in vivo study, 1 % T-5224 ointment was topically applied for 8 days to the ears of 2,4 dinitrofluorobenzene challenged AD-like dermatitis model mice. Baricitinib, a conventional therapeutic agent Janus kinase (JAK) inhibitor, was also topically applied. In the in vitro study, human epidermal keratinocytes were treated with T-5224 and stimulated with AD-related cytokines.
RESULTS:
AP-1/c-Jun was phosphorylated at skin lesions in AD patients. In vivo, topical T-5224 application inhibited ear swelling (P < 0.001), restored filaggrin (Flg) expression (P < 0.01), and generally suppressed immune-related pathways. T-5224 significantly suppressed Il17a and l17f expression, whereas baricitinib did not. Baricitinib suppressed Il4, Il19, Il33 and Ifnb expression, whereas T-5224 did not. Il1a, Il1b, Il23a, Ifna, S100a8, and S100a9 expression was cooperatively downregulated following the combined use of T-5224 and baricitinib. In vitro, T-5224 restored the expression of FLG and loricrin (LOR) (P < 0.05) and suppressed IL33 expression (P < 0.05) without affecting cell viability and cytotoxicity.
CONCLUSIONS:
Topical T-5224 ameliorates clinical manifestations of AD-like dermatitis in mice. The effect of this inhibitor is amplified via combined use with JAK inhibitors.
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