Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages

Yorihiro Iwasaki, Takayoshi Suganami, Rumi Hachiya, Ibuki Shirakawa, Misa Kim-Saijo, Miyako Tanaka, Miho Hamaguchi, Takako Takai-Igarashi, Michikazu Nakai, Yoshihiro Miyamoto, Yoshihiro Ogawa

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Chronic inflammation is a molecular element of the metabolic syndrome and type 2 diabetes. Saturated fatty acids (SFAs) are considered to be an important proinflammatory factor. However, it is still incompletely understood how SFAs induce proinflammatory cytokine expression. Hereby we report that activating transcription factor (ATF) 4, a transcription factor that is induced downstream of metabolic stresses including endoplasmic reticulum (ER) stress, plays critical roles in SFA-induced interleukin-6 (Il6) expression. DNA microarray analysis using primary macrophages revealed that the ATF4 pathway is activated by SFAs. Haploinsufficiency and short hairpin RNA-based knockdown of ATF4 in macrophages markedly inhibited SFA- and metabolic stress-induced Il6 expression. Conversely, pharmacological activation of the ATF4 pathway and overexpression of ATF4 resulted in enhanced Il6 expression. Moreover, ATF4 acts in synergy with the Toll-like receptor-4 signaling pathway, which is known to be activated by SFAs. At a molecular level, we found that ATF4 exerts its proinflammatory effects through at least two different mechanisms: ATF4 is involved in SFAinduced nuclear factor-kB activation; and ATF4 directly activates the Il6 promoter. These findings provide evidence suggesting that ATF4 links metabolic stress and Il6 expression in macrophages.

Original languageEnglish
Pages (from-to)152-161
Number of pages10
JournalDiabetes
Volume63
Issue number1
DOIs
Publication statusPublished - Jan 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Iwasaki, Y., Suganami, T., Hachiya, R., Shirakawa, I., Kim-Saijo, M., Tanaka, M., Hamaguchi, M., Takai-Igarashi, T., Nakai, M., Miyamoto, Y., & Ogawa, Y. (2014). Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages. Diabetes, 63(1), 152-161. https://doi.org/10.2337/db13-0757