RGD Reference Report - Interleukin-17 Signaling in Inflammatory, Kupffer, and Hepatic Stellate Cells Exacerbates Liver Fibrosis in Mice. - Rat Genome Database

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Interleukin-17 Signaling in Inflammatory, Kupffer, and Hepatic Stellate Cells Exacerbates Liver Fibrosis in Mice.

Authors: Meng, F  Wang, K  Aoyama, T  Grivennikov, SI  Paik, Y  Scholten, D  Cong, M  Iwaisako, K  Liu, X  Zhang, M  Osterreicher, CH  Stickel, F  Ley, K  Brenner, DA  Kisseleva, T 
Citation: Meng F, etal., Gastroenterology. 2012 Jun 8.
RGD ID: 6892914
Pubmed: PMID:22687286   (View Abstract at PubMed)
PMCID: PMC3635475   (View Article at PubMed Central)
DOI: DOI:10.1053/j.gastro.2012.05.049   (Journal Full-text)

BACKGROUND & AIMS: Interleukin (IL)-17 signaling has been implicated in lung and skin fibrosis. We examined the role of IL-17 signaling in the pathogenesis of liver fibrosis in mice. METHODS: Using cholestatic and hepatotoxic models of liver injury, we compared the development of liver fibrosis in wild-type mice with that of IL-17RA(-/-) mice and of bone marrow chimeric mice devoid of IL-17 signaling in immune and Kupffer cells (IL-17RA(-/-) to wild-type and IL-17A(-/-) to wild-type mice) or liver resident cells (wild-type to IL-17RA(-/-) mice). RESULTS: In response to liver injury, levels of Il-17A and its receptor increased. IL-17A increased appeared to promote fibrosis by activating inflammatory and liver resident cells. IL-17 signaling facilitated production of IL-6, IL-1, and tumor necrosis factor-alpha by inflammatory cells and increased the expression of transforming growth factor-1, a fibrogenic cytokine. IL-17 directly induced production of collagen type I in hepatic stellate cells by activating the signal transducers and activators of transcription (Stat3) signaling pathway. Mice devoid of Stat3 signaling in hepatic stellate cells (GFAPStat3(-/-) mice) were less susceptible to fibrosis. Furthermore, deletion of IL-23 from immune cells attenuated liver fibrosis, whereas deletion of IL-22 exacerbated fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protected mice from bile duct ligation-induced liver fibrosis. CONCLUSIONS: IL-17 induces liver fibrosis through multiple mechanisms in mice. Reagents that block these pathways might be developed as therapeutics for patients with cirrhosis.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
STAT3Humanliver cirrhosis  ISOStat3 (Mus musculus) RGD 
Stat3Ratliver cirrhosis  ISOStat3 (Mus musculus) RGD 
Stat3Mouseliver cirrhosis  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Stat3  (signal transducer and activator of transcription 3)

Genes (Mus musculus)
Stat3  (signal transducer and activator of transcription 3)

Genes (Homo sapiens)
STAT3  (signal transducer and activator of transcription 3)


Additional Information