Activated hepatic stellate cells mediate the differentiation of macrophages

Jonathan Chang, Tadakazu Hisamatsu, Katsuyoshi Shimamura, Kazuaki Yoneno, Masayuki Adachi, Hiroshi Naruse, Toru Igarashi, Hajime Higuchi, Katsuyoshi Matsuoka, Mina T. Kitazume, Setsu Ando, Nobuhiko Kamada, Takanori Kanai, Toshifumi Hibi

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)


Aim: Liver macrophages play integral roles in both the progression and resolution of hepatic inflammation and fibrosis, comprising opposing functions that largely coincide with the activation state of nearby hepatic stellate cells (HSC). While cross-talk between HSC and macrophages may be essential at various stages of inflammation and fibrogenesis, many facets of this interaction have yet to be thoroughly explored. Here, we examine the potential roles of HSC-derived signaling molecules as mediators of liver macrophage differentiation. Methods: Human peripheral blood mononuclear cells (PBMC) were differentiated to macrophages in the presence or absence of cultured HSC-derived conditioned media. The phenotype of resulting macrophages was characterized by examination of cell surface marker expression, antigen-presenting capabilities and cytokine secretion. Results: Conditioned media from activated human HSC promoted the differentiation of a unique set of macrophages that differed in morphology and function from both classical (M1) and alternative (M2) macrophages, expressing increased levels of CD14 and CD16, as well as a distinct interleukin (IL)-6high/IL-10low/transforming growth factor (TGF)-βhigh expression profile. These macrophages expressed high levels of CD206, CD209, CD80 and human leukocyte antigen DR, though no significant increases in antigen presentation were apparent. HSC-derived macrophages exhibited specific activation of p38 mitogen-activated protein kinase, and inhibition of this activation by p38 inhibitors during differentiation effectively reversed increases in IL-6 and TGF-β. Conclusion: The present results suggest that HSC-derived signaling molecules promote differentiation of liver macrophages with both pro-inflammatory and profibrotic functions. Furthermore, these effects appear to be mediated, at least partially, in a p38-dependent manner.

Original languageEnglish
Pages (from-to)658-669
Number of pages12
JournalHepatology Research
Issue number6
Publication statusPublished - 2013 Jun


  • Fibrosis
  • Hepatic stellate cell
  • Interleukin-6
  • Macrophage
  • P38 mitogen-activated protein kinase
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Hepatology
  • Infectious Diseases


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