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Regulation of matrix metalloproteinase-1 and alpha-smooth muscle actin expression by interleukin-1 alpha and tumour necrosis factor alpha in hepatic stellate cells

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Abstract

Hepatic stellate cells (HSCs) are key players in liver fibrosis and regeneration via collagen degradation and synthesis. These phenomena involve inflammatory cytokines released from non-parenchymal liver cells such as Kupffer cells. Although the effects of individual cytokines on many cell types have been investigated in various conditions, such as inflammation and tissue fibrosis, investigating the effect of combined cytokines would further our understanding of the regulatory mechanisms in tissue fibrosis. Here, we report the effect of multiple cytokine combinations on primary HSCs. We first examined the effect of individual cytokines and then the simultaneous exposure of different cytokines, including interleukin-6 (IL-6), IL-1 alpha (IL-1α), platelet-derived growth factor (PDGF), tumour necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β), on matrix metalloproteinase-1 (MMP1) gene expression in primary HSCs. We observed that the combination of all five cytokines induced higher levels of MMP1 gene expression. Of these cytokines, TNF-α and IL-1α were found to be the key cytokines for not only inducing MMP1 expression, but also increasing α-smooth muscle actin gene expression. In conclusion, the combined treatment of TNF-α and IL-1α on HSCs had an enhanced effect on the expression of the fibrotic genes, MMP1 and α-smooth muscle actin, so appears to be an important regulator for tissue regeneration. This finding suggests that stimulation with combined anti-fibrotic cytokines is a potential approach in the development of a novel therapy for the recovery of liver fibrosis.

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Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka-shi, Fukuoka, 819-0395, Japan

    Asami Inoue, Satoru Kuhara & Kosuke Tashiro

  2. Department of Bioscience and Biotechnology, Faculty of agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka-shi, Fukuoka, 812-8581, Japan

    Kenichi Obayashi, Yuka Sonoda, Satoru Kuhara & Kosuke Tashiro

  3. Research Center for Innovative Cancer Therapy, Kurume University, 67 Asahi-machi, Kurume, 830-0011, Japan

    Anna Nakamura

  4. Asakura Medical Association Hospital, 422-1 Raiha, Asakura, Fukuoka, 838-0069, Japan

    Takato Ueno

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  1. Asami Inoue
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  2. Kenichi Obayashi
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  3. Yuka Sonoda
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  4. Anna Nakamura
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  5. Takato Ueno
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  6. Satoru Kuhara
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  7. Kosuke Tashiro
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Correspondence to Kosuke Tashiro.

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Inoue, A., Obayashi, K., Sonoda, Y. et al. Regulation of matrix metalloproteinase-1 and alpha-smooth muscle actin expression by interleukin-1 alpha and tumour necrosis factor alpha in hepatic stellate cells. Cytotechnology 69, 461–468 (2017). https://doi.org/10.1007/s10616-016-9948-3

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  • DOI: https://doi.org/10.1007/s10616-016-9948-3

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