ERK and p38 MAPK, but not NF-κB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts

Motoaki Sano, Keiichi Fukuda, Toshihiko Sato, Haruko Kawaguchi, Makoto Suematsu, Satoshi Matsuda, Shigeo Koyasu, Hideo Matsui, Keiko Yamauchi-Takihara, Masaki Harada, Yoshihiko Saito, Satoshi Ogawa

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Abstract

We recently reported that angiotensin II (Ang II) induced IL-6 mRNA expression in cardiac fibroblasts, which played an important role in Ang II-induced cardiac hypertrophy in paracrine fashion. The present study investigated the regulatory mechanism of Ang II-induced IL-6 gene expression, focusing especially on reactive oxygen species (ROS)-mediated signaling in cardiac fibroblasts. Ang II increased intracellular ROS in cardiac fibroblasts, and the increase was completely inhibited by the AT-1 blocker candesartan and the NADH/NADPH oxidase inhibitor diphenyleneiodonium (DPI). We first confirmed that antioxidant N-acetylcysteine, superoxide scavenger Tiron, and DPI suppressed Ang II-induced IL-6 expression. Because we observed that exogenous H2O2 also increased IL-6 mRNA, the signaling pathways downstream of Ang II and exogenous H2O2 were compared. Ang II, as well as exogenous H2O2, activated ERK, p38 MAPK, and JNK, which were significantly inhibited by N-acetylcysteine and DPI. In contrast with exogenous H2O2, however, Ang II did not influence phosphorylation and degradation of IκB-α/β or nuclear translocation of p65, nor did it increase NF-κB promoter activity. PD98059 and SB203580 inhibited Ang II-induced IL-6 expression. Truncation and mutational analysis of the IL-6 gene promoter showed that CRE was an important cis-element in Ang II-induced IL-6 gene expression. NF-κB-binding site was important for the basal expression of IL-6, but was not activated by Ang II. Ang II phosphorylated CREB through the ERK and p38 MAPK pathway in a ROS-sensitive manner. Collectively, these data indicated that Ang II stimulated ROS production via the AT1 receptor and NADH/NADPH oxidase, and that these ROS mediated activation of MAPKs, which culminated in IL-6 gene expression through a CRE-dependent, but not NF-κB-dependent, pathway in cardiac fibroblasts.

Original languageEnglish
Pages (from-to)661-669
Number of pages9
JournalCirculation research
Volume89
Issue number8
DOIs
Publication statusPublished - 2001 Oct 12

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Keywords

  • Angiotensin II
  • Cardiac fibroblast
  • Interleukin-6
  • Mitogen-activated protein kinase
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Sano, M., Fukuda, K., Sato, T., Kawaguchi, H., Suematsu, M., Matsuda, S., Koyasu, S., Matsui, H., Yamauchi-Takihara, K., Harada, M., Saito, Y., & Ogawa, S. (2001). ERK and p38 MAPK, but not NF-κB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts. Circulation research, 89(8), 661-669. https://doi.org/10.1161/hh2001.098873