GLI-fully Responsive to Inflammatory Cytokines
| Autor: | Spencer G. Willet |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
WT
wild type Interleukin-1beta RC799-869 KIF3A Kinesin II family member 3A SHH sonic hedgehog Mice Helicobacter dsddc1 wild-type C57BL/6 mice Pyloric Antrum Medicine IFN-γ interferon-γ IFN-γ Original Research SPEM spasmolytic polypeptide-expressing metaplasia digestive oral and skin physiology Gastroenterology ELISA enzyme-linked immunosorbent assay Diseases of the digestive system. Gastroenterology Editorial TX tamoxifen Cytokines GC gastric cancer qPCR quantitative polymerase chain reaction DOX doxycycline Mice Transgenic Antiviral Agents digestive system Zinc Finger Protein GLI1 Helicobacter Infections Proinflammatory cytokine GLI2 glioma-associated oncogene family zinc finger 2 Interferon-gamma Text mining IL1β interleukin-1β Gastrins Animals Hedgehog Proteins Cilia KIF3A Th1 T helper cell 1 Hyperplasia Helicobacter pylori Hepatology business.industry digestive system diseases Mice Inbred C57BL Gastric Cancer Immunology Hedgehog Signaling business |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 11, Iss 5, Pp 1545-(2021) Cellular and Molecular Gastroenterology and Hepatology |
| Popis: | Background & Aims Helicobacter pylori infection in humans typically begins with colonization of the gastric antrum. The initial Th1 response occasionally coincides with an increase in gastrin secretion. Subsequently, the gastritis segues to chronic atrophic gastritis, metaplasia, dysplasia and distal gastric cancer. Despite these well characterized clinical events, the link between inflammatory cytokines and non-cardia gastric cancer remains difficult to study in mouse models. Prior studies have demonstrated that overexpression of the Hedgehog (HH) effector GLI2 induces loss of gastrin (atrophy) and antral hyperplasia. To determine the link between specific cytokines, HH signaling and pre-neoplastic changes in the gastric antrum. Methods Mouse lines were created to conditionally direct IL1β or IFN-γ to the antrum using the Gastrin-CreERT2 and Tet activator. Primary cilia, which transduces HH signaling, on G cells were disrupted by deleting the ciliary motor protein KIF3a. Phenotypic changes were assessed by histology and western blots. A subclone of GLUTag enteroendocrine cells selected for gastrin expression and the presence of primary cilia was treated with recombinant SHH, IL1β or IFN-γ with or without kif3a siRNA. Results IFN-γ increased gastrin and induced antral hyperplasia. However, antral expression of IL1β suppressed tissue and serum gastrin, while also inducing antral hyperplasia. IFN-γ treatment of GLUTAg cells suppressed GLI2 and induced gastrin, without affecting cilia length. By contrast, IL1β treatment doubled primary cilia length, induced GLI2 and suppressed gastrin gene expression. Knocking down kif3a in GLUTAg cells mitigated SHH or IL1β suppression of gastrin. Conclusions Overexpression of IL1β in the antrum was sufficient to induce antral hyperplasia coincident with suppression of gastrin via primary cilia. ORCID: #0000-0002-6559-8184 Graphical abstract |
| Databáze: | OpenAIRE |
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