BACKGROUND: Human interleukin-22 (IL-22) is known as a "dual function" cytokine that acts as a master regulator to maintain homeostasis, structural integrity of the intestinal epithelial barrier, and shielding against bacterial pathogens. On the other hand, the overexpression of IL-22 is associated with hyper-proliferation and recruitment of pathologic effector cells, leading to tissue damage and chronic inflammation in specific diseases including inflammatory bowel disease (IBD). To study a role of IL-22-mediated signaling axis during intestinal inflammation, we generated a set of small protein blockers of IL-22R1 and verified their inhibitory potential on murine model of colitis. METHODS: We used directed evolution of proteins to identify binders of human IL-22 receptor alpha (IL-22R1), designated as ABR ligands. This approach combines the assembly of a highly complex combinatorial protein library derived from small albumin-binding domain scaffold and selection of promising protein variants using ribosome display followed by large-scale ELISA screening. The binding affinity and specificity of ABR variants were analyzed on transfected HEK293T cells by flow cytometry and LigandTracer. Inhibitory function was further verified by competition ELISA, HEK-Blue IL-22 reporter cells, and murine dextran sulfate sodium (DSS)-induced colitis. RESULTS: We demonstrate that ABR specifically recognizes transgenic IL-22R1 expressed on HEK293T cells and IL-22R1 on TNFα/IFNγ-activated HaCaT cells. Moreover, some ABR binders compete with the IL-22 cytokine and function as IL-22R1 antagonists in HEK-Blue IL22 reporter cells. In a murine model of DSS-induced acute intestinal inflammation, daily intraperitoneal administration of the best IL-22R1 antagonist, ABR167, suppressed the development of clinical and histological markers of colitis including prevention of mucosal inflammation and architecture deterioration. In addition, ABR167 reduces the DSS-induced increase in mRNA transcript levels of inflammatory cytokines such as IL-1β, IL-6, IL-10, and IL-17A. CONCLUSIONS: We developed small anti-human IL-22R1 blockers with antagonistic properties that ascertain a substantial role of IL-22-mediated signaling in the development of intestinal inflammation. The developed ABR blockers can be useful as a molecular clue for further IBD drug development.

• Klíčová slova
• Experimental colitis, Immune suppression, Inflammatory bowel disease, Interleukin-22, Protein engineering,
• MeSH
• HEK293 buňky MeSH
• interleukin 22 MeSH
• interleukiny genetika   metabolismus   MeSH
• kolitida * chemicky indukované   patologie   metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• receptory interleukinů * metabolismus   genetika   MeSH
• síran dextranu * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• interleukin 22 MeSH
• interleukin-22 receptor MeSH Prohlížeč
• interleukiny MeSH
• receptory interleukinů * MeSH
• síran dextranu * MeSH

BACKGROUND: Interleukin-22 (IL-22) is a pro-inflammatory cytokine released during the immune response in chronic liver injury. Although IL-22 mediates tissue regeneration, its uncontrolled production may generate a carcinogenic environment resulting in hepatocellular carcinoma (HCC). This study aims to identify the effect of IL-22 on anti-apoptotic and metastatic genes and the molecular pathways responsible for IL-22-mediated hepatic carcinogenesis. METHODS AND RESULTS: Three cancerous liver lines, HepG2, SNU-387, Huh7, and one normal liver line, THLE2, were treated with IL-22. RT-qPCR analysis was conducted to study the role of IL-22 in altering the expression levels of anti-apoptotic genes, MCL-1 and BCL-2, and metastatic genes, MMP-7 and MMP-9. A significant increase in expression levels of these genes was observed after IL-22 treatment. Furthermore, to explore the major pathways involved in IL-22-mediated upregulation of anti-apoptotic and metastatic genes, cells were treated with inhibitors of JAK/STAT and PI3K/AKT pathways along with IL-22. Resultantly, a significant decrease in expression levels of target genes was observed, indicating the involvement of JAK/STAT and PI3K/AKT signaling cascades in IL-22-mediated oncogenesis. Finally, Cell Scratch assay was performed to check the effect of IL-22 and inhibitors of JAK/STAT and PI3K/AKT on the metastatic potential of liver cells. While migration was observed in Huh7 and THLE2 cells treated with IL-22, no migration was observed in cells treated with IL-22 along with JAK/STAT and PI3K/AKT inhibitors. Results indicate that IL-22 encourages metastasis in HCC cells via the JAK/STAT and PI3K/AKT pathways. CONCLUSION: Results showed that IL-22 upregulates anti-apoptotic and metastatic genes in HCC through JAK/STAT and PI3K/AKT signaling pathways.

• Klíčová slova
• Hepatocellular carcinoma, IL-22, JAK/STAT pathway, PI3K/AKT pathway, Proinflammatory cytokine,
• MeSH
• 1-fosfatidylinositol-3-kinasa metabolismus   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• hepatocelulární karcinom * metabolismus   MeSH
• interleukin 22 MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory jater * metabolismus   MeSH
• proliferace buněk genetika   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1-fosfatidylinositol-3-kinasa MeSH
• fosfatidylinositol-3-kinasy MeSH
• protoonkogenní proteiny c-akt MeSH

Wound healing and tissue regeneration is an intricate biological process that involves repair of cellular damage and maintenance of tissue integrity. Cascades involved in wound healing and tissue regeneration highly overlap with cancer causing pathways. Usually, subsequent tissue damage events include release of a number of cytokines to accomplish post-trauma restoration. IL-22 is one of the cytokines that are immediately produced to initiate immune response against several tissue impairments. IL-22 is a fundamental mediator in inflammation, mucous production, protective role against pathogens, wound healing, and tissue regeneration. However, accumulating evidence suggests pivotal role of IL-22 in instigation of various cancers due to its pro-inflammatory and tissue repairing activity. In this review, we summarize how healing effects of IL-22, when executed in an uncontrollable fashion can lead to carcinogenesis.

• Klíčová slova
• IL22-producing cells, carcinogenesis and metastasis, innate immune response and inflammation, tissue regeneration, wound healing—physiopathology,
• MeSH
• hlen metabolismus   MeSH
• hojení ran fyziologie   MeSH
• humanizované monoklonální protilátky terapeutické užití   MeSH
• infekce imunologie   metabolismus   MeSH
• interleukin 22 MeSH
• interleukiny škodlivé účinky   antagonisté a inhibitory   nedostatek   fyziologie   MeSH
• karcinogeneze MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• myši MeSH
• nádory etiologie   patofyziologie   MeSH
• neutralizující protilátky terapeutické užití   MeSH
• přirozená imunita fyziologie   MeSH
• psoriáza farmakoterapie   imunologie   MeSH
• receptory interleukinů fyziologie   MeSH
• regenerace fyziologie   MeSH
• revmatoidní artritida farmakoterapie   imunologie   MeSH
• T-lymfocyty - podskupiny imunologie   metabolismus   MeSH
• zánět patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• fezakinumab MeSH Prohlížeč
• humanizované monoklonální protilátky MeSH
• IL22RA2 protein, human MeSH Prohlížeč
• interleukin-22 receptor MeSH Prohlížeč
• interleukiny MeSH
• neutralizující protilátky MeSH
• receptory interleukinů MeSH

Hepatic stellate cells (HSCs), also known as perisinusoidal cells, are pericytes found in the perisinusoidal space of the liver. HSCs are the major cell type involved in liver fibrosis, which is the formation of scar tissue in response to liver damage. When the liver is damaged, stellate cells can shift into an activated state, characterized by proliferation, contractility and chemotaxis. The activated HSCs secrete collagen scar tissue, which can lead to cirrhosis. Recent studies have shown that in vivo activation of HSCs by fibrogenic agents can eventually lead to senescence of these cells, which would contribute to reversal of fibrosis although it may also favor the insurgence of liver cancer. HSCs in their non-active form store huge amounts of retinoic acid derivatives in lipid droplets, which are progressively depleted upon cell activation in injured liver. Retinoic acid is a metabolite of vitamin A (retinol) that mediates the functions of vitamin A, generally required for growth and development. The precise function of retinoic acid and its alterations in HSCs has yet to be elucidated, and nonetheless in various cell types retinoic acid and its receptors (RAR and RXR) are known to act synergistically with peroxisome proliferator-activated receptor gamma (PPAR-gamma) signaling through the activity of transcriptional heterodimers. Here, we review the recent advancements in the understanding of how retinoic acid signaling modulates the fibrogenic potential of HSCs and proposes a synergistic combined action with PPAR-gamma in the reversal of liver fibrosis.

• Klíčová slova
• Fibrogenesis, Hepatic stellate cells, Retinoic acid,
• MeSH
• antitumorózní látky MeSH
• jaterní cirhóza patofyziologie   MeSH
• jaterní hvězdicovité buňky fyziologie   MeSH
• keratolytika MeSH
• lidé MeSH
• PPAR gama metabolismus   MeSH
• signální transdukce * MeSH
• tretinoin metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky MeSH
• keratolytika MeSH
• PPAR gama MeSH
• tretinoin MeSH