Pro-inflammatory cytokines suppress HYBID (hyaluronan (HA) -binding protein involved in HA depolymerization/KIAA1199/CEMIP) -mediated HA metabolism in human skin fibroblasts

• Published in: Biochemical and biophysical research communications 2021-02, Vol.539, p.77-82
• Main Authors: Sato, Shinya, Mizutani, Yukiko, Yoshino, Yuta, Masuda, Manami, Miyazaki, Megumi, Hara, Hideaki, Inoue, Shintaro
• Format: Article
• Language: English
• Subjects: CEMIP; Hyaluronan depolymerization; Hyaluronidase; HYBID; Pro-inflammatory cytokine; TMEM2
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2020.12.082

In the skin, the metabolism of hyaluronan (HA) is highly regulated. Aging leads to chronic low-grade inflammation, which is characterized by elevated levels of pro-inflammatory cytokines; however, the relationship between inflammation and HA metabolism is not clear. Herein, we investigated the effects of a mixture of pro-inflammatory cytokines containing TNF-α, IL-1β, and IL-6 on HA metabolism in human skin fibroblasts. Treatment with the cytokine mixture for 24 h suppressed HA depolymerization via downregulation of HYBID (HA-binding protein involved in HA depolymerization/KIAA1199/CEMIP) and promoted HA synthesis via upregulation of HAS2 in human skin fibroblasts. Moreover, HAS2-dependent HA synthesis was driven mainly by IL-1β with partial contribution from TNF-α. Transmembrane protein 2 (TMEM2/CEMIP2), which was previously reported as a candidate hyaluronidase, was upregulated by the cytokine mixture, suggesting that TMEM2 might not function as a hyaluronidase in human skin fibroblasts. Furthermore, the effects of the cytokine mixture on HA metabolism were observed in fibroblasts after 8 days of treatment with cytokines during three passages. Thus, we have shown that HYBID-mediated HA metabolism is negatively regulated by the pro-inflammatory cytokine mixture, providing novel insights into the relationship between inflammation and HA metabolism in the skin. •Effects of pro-inflammatory cytokines on HA metabolism were studied in fibroblasts.•IL-1β inhibited HA depolymerization by decreasing HYBID expression.•IL-1β and TNF-α increased TMEM2 expression, but HA depolymerization was not increased.•IL-1β and TNF-α up-regulated HAS2, and increased the amount of HA.•Neither IL-6 nor IL-8 affected HA metabolism in human skin fibroblasts.