Both MAPK and STAT3 signal transduction pathways are necessary for IL-6-dependent hepatic stellate cells activation
| Autor: | Irina Tachlytski, Ziv Ben-Ari, Polina Kagan, Maya Sultan, Michal Safran |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cell signaling lcsh:Medicine Signal transduction Pathology and Laboratory Medicine Mice 0302 clinical medicine Medicine and Health Sciences lcsh:Science STAT3 Immune Response Mice Inbred ICR Multidisciplinary biology Chemistry Liver Diseases Signaling cascades Cell biology STAT signaling 030220 oncology & carcinogenesis Liver Fibrosis Phosphorylation Mitogen-Activated Protein Kinases Research Article STAT3 Transcription Factor MAPK signaling cascades p38 mitogen-activated protein kinases Immunology Gastroenterology and Hepatology 03 medical and health sciences Signs and Symptoms Downregulation and upregulation Diagnostic Medicine Hepatic Stellate Cells Animals Inflammation Biology and life sciences Interleukin-6 lcsh:R Fibrosis Fatty Liver 030104 developmental biology Hepatic stellate cell biology.protein lcsh:Q Developmental Biology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 12, Iss 5, p e0176173 (2017) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0176173 |
| Popis: | Background During liver injury, hepatic stellate cells (HSCs) can undergo activation and transform into alpha-smooth muscle actin (αSMA)-expressing contractile myofibroblast-like cells, leading to deposition of excessive scar matrix. We have recently demonstrated that depletion of adenosine deaminase acting on double-stranded RNA (ADAR1) from mouse hepatocytes leads to HSC activation and induction of inflammation and hepatic fibrosis that is mediated by interleukin 6 (IL-6). Our aim was to identify and characterize the molecular pathways involved in the direct, inflammation-independent activation of HSCs by IL-6. Methods Primary HSCs were isolated from mouse livers. mRNA levels of αSMA and Col1a were analyzed using qRT-PCR. Protein levels of αSMA, MAPK, p-MAPK, p38, p-p38, STAT3 and p-STAT3 were assessed by Western Blot analysis. The effect of specific signal transduction pathway inhibitors (i.e., SB203580 (P-38 inhibitor), U0126 (MAPK inhibitor), S3I-201 (STAT3 inhibitor) and Ruxolitinib (Jak1/2 inhibitor)) was also studied. Results Primary HSCs treated with IL-6 demonstrated upregulation of αSMA and Col1a mRNA levels as well as increased αSMA protein levels. Moreover, the phenotypic transition of quiescent HSCs toward myofibroblast-like cells was noted upon administration of IL-6 and not in untreated samples. In addition, the phosphorylation levels of p38, MAPK and STAT3 increased 30 minutes after treatment, and was followed by a decline in the phosphorylation levels 2–4 hours post-treatment. However, addition of specific signal transduction pathway inhibitors curbed this effect, and resulted in αSMA and Col1a expression levels similar to those measured in untreated control samples. Conclusion IL-6 can directly induce the transition of HSCs toward myofibroblast-like cells. The effect is mediated by the activation of both MAPK and JAK/STAT signaling pathways. Elimination of either MAPK or JAK/STAT signaling pathways inhibits HSC stimulation. These results might pave the road toward the development of potential therapeutic interventions for hepatic fibrosis. |
| Databáze: | OpenAIRE |
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