Differential regulation of eotaxin-1/CCL11 and eotaxin-3/CCL26 production by the TNF-α and IL-4 stimulated human lung fibroblast

Akiko Rokudai, Yasuhito Terui, Ryoko Kuniyoshi, Yuji Mishima, Yuko Mishima, Eriko Aizu-Yokota, Yoshiko Sonoda, Tadashi Kasahara, Kiyohiko Hatake

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Allergic asthma and allergic dermatitis are chronic inflammatory diseases and are characterized by an accumulation of eosinophils at sites of inflammation. Eotaxin-1/CCL11 and eotaxin-3/CCL26 are members of the CC chemokine family, which are known to be potent chemoattractants for eosinophils. We observed that a human lung fibroblast, HFL-1 produces eotaxin-1 and -3 in response to TNF-α plus IL-4 stimulation, accompanied with NF-κB and STAT6 activation. We explored which signaling pathways are operative in the production of eotaxin-1 and -3 using several inhibitors. Eotaxin-1/CCL11 production was inhibited by a p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, but not by the MEK (MAPK/ERK kinase) inhibitors, PD98059 and U0126. In contrast, eotaxin-3/CCL26 production was inhibited similarly by PD98059 as well as U0126 and SB203580. In addition, two proteasome inhibitors, N-acetyl-leucyl-leucyl-norleucinal (ALLN) and bortezomib with significant inhibitory activity on NF-κB activation, inhibited eotaxin-1/CCL11 production with IC50 8 μM for ALLN and IC50 16 nM for bortezomib. In contrast, eotaxin-3/CCL26 production was not inhibited significantly up to 10 μM of ALLN (IC50 16 μM) and up to 10 nM of bortezomib (IC50 11 nM), giving inhibition of eotaxin-3/CCL26 less sensitive than eotaxin-1/CCL11 production by the proteasome inhibitors. Synergistic inhibition was observed among lower doses of SB203580 and proteasome inhibitors, particularly in the eotaxin-1/CCL11 production. No such prominent synergism was found on the eotaxin-3/CCL26 production. The suppression of eotaxin family production by these inhibitors may be efficacious against allergic diseases.

Original languageEnglish
Pages (from-to)1102-1109
Number of pages8
JournalBiological and Pharmaceutical Bulletin
Volume29
Issue number6
DOIs
Publication statusPublished - 2006 Jun 1

Keywords

  • Eotaxin-1
  • Eotaxin-3
  • Lung fibroblast
  • NF-κB activation
  • Proteasome inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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