RRC ID 44620
Author Iwasaki Y, Suganami T, Hachiya R, Shirakawa I, Kim-Saijo M, Tanaka M, Hamaguchi M, Takai-Igarashi T, Nakai M, Miyamoto Y, Ogawa Y.
Title Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages.
Journal Diabetes
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.
Volume 63(1)
Pages 152-61
Published 2014-1-1
DOI 10.2337/db13-0757
PII db13-0757
PMID 23990363
MeSH Activating Transcription Factor 4 / genetics Activating Transcription Factor 4 / metabolism* Animals Fatty Acids / metabolism Haploinsufficiency Inflammation / genetics Inflammation / metabolism Interleukin-6 / genetics Interleukin-6 / metabolism* Macrophages / metabolism* Mice Mice, Knockout NF-kappa B / metabolism Promoter Regions, Genetic Signal Transduction / physiology* Stress, Physiological / physiology* Toll-Like Receptor 4 / genetics Toll-Like Receptor 4 / metabolism eIF-2 Kinase / genetics eIF-2 Kinase / metabolism
IF 7.72
Times Cited 42
Human and Animal Cells RAW 264(RCB0535)