Activating Transcription Factor 4 Links Metabolic Stress to Interleukin-6 Expression in Macrophages

  1. Yoshihiro Ogawa1,3
  1. 1Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
  2. 2Department of Organ Network and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
  3. 3Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo, Japan
  4. 4Center for Diabetes and Endocrinology, The Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan
  5. 5Department of Health Record Informatics, Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan
  6. 6Department of Preventive Medicine and Epidemiologic Informatics, National Cerebral and Cardiovascular Center, Osaka, Japan
  7. 7Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan
  8. 8Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Tokyo, Japan
  9. 9Japan Society for the Promotion of Science for Young Scientists, Tokyo, Japan
  1. Corresponding author: Takayoshi Suganami, suganami.mem{at}tmd.ac.jp, or Yoshihiro Ogawa, ogawa.mem{at}tmd.ac.jp.

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 SFA-induced nuclear factor-κB activation; and ATF4 directly activates the Il6 promoter. These findings provide evidence suggesting that ATF4 links metabolic stress and Il6 expression in macrophages.

Footnotes

  • Received May 10, 2013.
  • Accepted August 26, 2013.

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  1. Diabetes vol. 63 no. 1 152-161
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