AP-1 activation through endogenous H2O2 generation by alveolar macrophages

Karen E. Iles, Dale A. Dickinson, Nobuo Watanabe, Takeo Iwamoto, Henry Jay Forman

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

Abstract

Reactive oxygen species released during the respiratory burst are known to participate in cell signaling. Here we demonstrate that hydrogen peroxide produced by the respiratory burst activates AP-1 binding. Stimulation of the macrophage cell line NR8383 with respiratory burst agonists ADP and C5a increased AP-1 binding activity. Importantly, this increase in binding was blocked by catalase, confirming mediation by endogenous H2O2. Moreover, exogenously added H2O2 mimicked the agonists, and also activated AP-1. Antibodies revealed that the activated AP-1 complex is composed predominantly of c-Fos/c-Jun heterodimers. Treatment of the cells with ADP, C5a and H2O2 (100 μM) all increased the phosphorylation of c-Jun. c-Fos protein was increased in cells treated with C5a or high dose (200 μM) H2O2, but not in cells treated with ADP. The MEK inhibitor, PD98059, partially blocked the C5a-mediated increase in AP-1 binding. A novel membrane-permeable peptide inhibitor of JNK, JNKi, also inhibited AP-1 activation. Together these data suggest that C5a-mediated AP-1 activation requires both the activation of the ERK and JNK pathways, whereas activation of the JNK pathway is sufficient to increase AP-1 binding with ADP. Thus, AP-1 activation joins the list of pathways for which the respiratory burst signals downstream events in the macrophage.

Original languageEnglish
Pages (from-to)1304-1313
Number of pages10
JournalFree Radical Biology and Medicine
Volume32
Issue number12
DOIs
Publication statusPublished - 2002 Jun 15

Keywords

  • Activator protein-1 (AP-1)
  • ERK
  • Fos
  • Free radicals
  • JNK
  • Jun
  • Mitogen-activated protein kinases (MAPK)
  • Respiratory burst
  • Signaling

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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