Background
Cytokines are involved in the communication between the various cell types of the immune system, among which interleukin (IL), a small peptide hormone that binds to a specific receptor, controls differentiation, proliferation, migration, and apoptosis of the corresponding target cells. Interleukin dysregulation can cause chronic inflammation, autoimmune disease, or tumor disease. Interleukin-23 (IL-23) is a central cytokine that controls the development of Th17 cells, and excessive IL-23 signaling can lead to autoimmune diseases. In addition to Th17 cells, other innate immune cells respond to IL-23, such as natural killer T-cells (NKTs) and innate lymphocytes (ILCs), which are also important for fighting infections and autoimmune lesions.
IL-23 is a member of the IL-12-type cytokine family and consists of IL-23p19 and p40. The IL-12 family consists of three heterodimeric cytokines (IL-12, IL-23, and IL-35), and within the IL-12 family, IL-12 and IL-23 share the p40 cytokine subunit and IL-12Rb1 as a chain of receptor complexes. In signaling, IL-23 triggers heterodimerization of IL-12Rb1 and IL-23R. Subsequently, signaling pathways including JAK/STAT, MAPK and PI3K are activated. In addition, the IL-6 and IL-12 families are closely related due to the structural similarity of the cytokines and their respective receptors.
Figure 1. Schematic illustration of the IL-12 and IL-23 receptor complexes
(Source: Floss DM, et al. 2015)
IL-23 is recognized as an important factor in the pathogenesis of many autoimmune inflammatory diseases and cancers, and targeting IL-23 is a potential treatment for psoriasis, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and cancer. Several drugs have been used as IL-23 antagonists to mitigate the side effects of treating diseases by inhibiting specific pathways involved in the pathogenesis of the disease. IL-12 drives the Th1 pathway characterized by the signature cytokines IFNγ and TNF and stimulates group 1 ILCs. In contrast, IL-23 promoted the Th17 pathway and stimulated group 3 ILCs and NKT. In studies on colon cancer, researchers have found that the cytokine IL-22 secreted by Th17 plays a role in promoting colon tumorigenesis, and that IL-23 antagonism may be relevant.
Figure 2. Overview of IL12 and IL23's pathways in the pathogenesis of inflammatory bowel disease
(Source: Parigi TL, et al. 2022)
Alternative Names
Anti-Mouse IL 23 (p19) Monoclonal antibody
Anti-Mouse Interleukin-23 (p19) Monoclonal antibody
References
- 1. Floss DM, et al. Insights into IL-23 biology: From structure to function. Cytokine Growth Factor Rev. 2015 Oct;26(5):569-78.
- 2. Parigi TL, et al. Blockade of IL-23: What is in the Pipeline? J Crohns Colitis. 2022 May 11;16(Supplement_2):ii64-ii72.
References
Tumor-promoting effect of IL-23 in mammary cancer mediated by infiltration of M2 macrophages and neutrophils in tumor microenvironment
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Authors: Nie, Wen; Yu, Ting; Sang, Yaxiong; Gao, Xiang
Abstract
Interleukin 23 (IL-23) is an inflammatory cytokine which plays a vital role in autoimmune diseases as well as in tumorigenesis. However, the role of IL-23 in tumor procession is still controversial and the underlying mechanism remains unclear. Here we established a stable cell line overexpressing IL-23 to prove that IL-23 promoted tumor growth and pulmonary metastasis through induction of tumor-related inflammation and absence of immune surveillance. IL-23 promotes tumor-associate inflammatory response such as infiltration of M2 macrophages, neutrophils and their elevated secretions of immunosuppressive cytolcines transforming growth factor-beta (TGF-beta), IL-10 and vascular endothelial growth factor (VEGF) into tumor tissues, meanwhile the increase of the matrix metalloprotease MMP9. In addition, IL-23 increases the expression of the endothelial marker CD31 and proliferative marker Ki67 in tumors. Moreover, IL23 induces immunosuppression though reducing the infiltration of CD4(+) and CD8(+)T cells into tumor tissues. In conclusion, IL-23 is a considerable molecular in tumor progression, which simultaneously facilitates processes of pro-tumor inflammation, such as angiogenesis, immunosuppressive cytolcines as well as infiltrations of M2 macrophages and neutrophils, and suppresses antitumor immune responses through reduction of CD4(+) T cells and CD8(+) T cells. (C) 2016 Elsevier Inc. All rights reserved.
The Exonuclease Trex2 Shapes Psoriatic Phenotype
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Authors: Manils, Joan; Casas, Eduard; Vina-Vilaseca, Arnau; Lopez-Cano, Marc; Diez-Villanueva, Anna; Gomez, Diana; Marruecos, Laura; Ferran, Marta; Benito, Carmen; Perrino, Fred W.; Vavouri, Tanya; de Anta, Josep Maria; Ciruela, Francisco; Soler, Concepcio
Abstract
Trex2 is a keratinocyte-specific 30-deoxyribonuclease that participates in the maintenance of skin homeostasis after DNA damage. Here, we show that this exonuclease is strongly upregulated in human psoriasis, a hyperproliferative and inflammatory skin disease. Similarly, the imiquimod (IMQ)-and Il23-induced mouse psoriasis was associated with a substantial upregulation of Trex2, which was recruited into fragmented chromatin in keratinocytes that were undergoing impaired proliferation, differentiation, and cell death, indicating an important role in DNA processing. Using Trex2 knockout mice, we have found that Trex2 deficiency attenuated IMQ-induced psoriasis-like skin inflammation and enhanced IMQ-induced parakeratosis. Also, Il23-induced ear swelling was diminished in Trex2 knockout mice in comparison with wild-type (wt) mice. Transcriptome analysis identified multiple genes that were deregulated by Trex2 loss after treatment with IMQ. Specifically, immune response genes and pathways normally associated with inflammation were down-regulated, whereas those related to skin differentiation and chromatin biology showed increased expression. Interestingly, Trex2 deficiency led to decreased IMQ-induced keratinocyte death via both cell autonomous and noncell autonomous mechanisms. Hence, our data indicate that Trex2 acts as a critical factor in the pathogenesis of psoriasis by promoting keratinocyte apoptosis and enucleation and thereby influencing skin immune responses.
COA
Publication 
Loading ......
