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IL-8 induces transdifferentiation of mature hepatocytes toward the cholangiocyte phenotype.

ABSTRACT: The adult mammalian liver exhibits a remarkable regenerative capacity, with different modes of regeneration according to the type and extent of injury. Hepatocyte-cholangiocyte biphenotypic liver progenitor cell populations appear under conditions of excessive injury. It has been reported that mature hepatocytes can transdifferentiate toward a cholangiocyte phenotype and be a cellular source of progenitor cell populations. Here, we determined that among various plasma cytokines, interleukin (IL)-8 levels were significantly elevated in acute liver failure and severe acute liver injury patients. In vitro assays revealed that administration of IL-8 homologues increases the expression of Sry HMG box protein 9 (SOX9). In liver biopsies of acute liver injury patients, we observed the appearance of SOX9-positive biphenotypic hepatocytes accompanied by elevation of plasma IL-8 levels. Our results suggest that IL-8 regulates the phenotypic conversion of mature hepatocytes toward a cholangiocyte phenotype.

SUBMITTER: Sasaki T

PROVIDER: S-EPMC6886300 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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IL-8 induces transdifferentiation of mature hepatocytes toward the cholangiocyte phenotype.

Sasaki Tokio T Suzuki Yuji Y Kakisaka Keisuke K Wang Ting T Ishida Kazuyuki K Suzuki Akiko A Abe Hiroaki H Sugai Tamotsu T Takikawa Yasuhiro Y

FEBS open bio 20191107 12

The adult mammalian liver exhibits a remarkable regenerative capacity, with different modes of regeneration according to the type and extent of injury. Hepatocyte-cholangiocyte biphenotypic liver progenitor cell populations appear under conditions of excessive injury. It has been reported that mature hepatocytes can transdifferentiate toward a cholangiocyte phenotype and be a cellular source of progenitor cell populations. Here, we determined that among various plasma cytokines, interleukin (IL) ...[more]

PMID: 31651102

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Project description:Background:Tumor-associated macrophage (TAM) is emerging as one of the important complications in cancer promotion. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, plays an active role in promoting M2 macrophage differentiation (TAMs are M2-like phenotypes). In this study, we aimed to evaluate that IL-17 stimulates key phenotypic and functional signatures of M2 macrophages associated with cancer progression in non-small-cell lung cancer (NSCLC) patients. Patients and methods:The markers and cytokines of M2 macrophages were detected in THP-1-derived macrophages and mouse peritoneal macrophages treated with IL-17. The activation of nuclear factor kappa B (NF-?B) and nuclear localization of p65 in IL-17-treated cells were investigated. The BAY11-7082 inhibitor and the siRNA of p65 were used to block the NF-?B activation. A total of 85 patients who underwent surgery for histologically verified NSCLC were enrolled in this study. The expression of IL-17 and M2 macrophage markers were assessed by immunostaining. Survivals were estimated using the Kaplan-Meier method. Results:The CD163 and CD206 cell surface markers and transforming growth factor beta (TGF-?), vascular endothelial growth factor (VEGF) and IL-10 of M2 macrophages were significantly increased in IL-17-treated THP-1-derived macrophages in a dose-dependent manner. IL-17 increased the mRNA levels of Arginase I and Fizz1, the phosphorylation of IkB? and nuclear localization of p65 (a subunit of NF-?B). The BAY11-7082 abrogated IL-17-induced CD206 and CD163 expression, TGF-?, VEGF, IL-10, Arginase I and Fizz1 expression and p65 nuclear translocation. Further experiments showed that IL-17 induced the expression of CD206, CD163, Arginase I, Fizz1 and Ym1 in mouse peritoneal macrophages that were inhibited by siRNA of p65. The immunostaining experiments on human NSCLC tissues indicated that high IL-17 expression was significantly correlated with CD163 and c-Maf. The intratumoral IL-17+ CD163+ c-Maf+ cells were associated with NSCLC progression. Conclusion:IL-17 stimulated macrophages to M2-like phenotypes via NF-?B activation. IL-17 may be a potential therapeutic target for NSCLC.

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IL-8 induces transdifferentiation of mature hepatocytes toward the cholangiocyte phenotype.

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IL-8 induces transdifferentiation of mature hepatocytes toward the cholangiocyte phenotype.

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