title: Activated hepatic stellate cells mediate the differentiation of macrophages.
abstract: OBJECTIVE
  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)-6(high) /IL-10(low) /transforming growth factor (TGF)-β(high) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chang
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Hisamatsu
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Shimamura
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yoneno
authors.forename: Masayuki
authors.initials: M
authors.lastname: Adachi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Naruse
authors.forename: Toru
authors.initials: T
authors.lastname: Igarashi
authors.forename: Hajime
authors.initials: H
authors.lastname: Higuchi
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Mina T
authors.initials: MT
authors.lastname: Kitazume
authors.forename: Setsu
authors.initials: S
authors.lastname: Ando
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kamada
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi