| RRC ID |
44620
|
| 著者 |
Iwasaki Y, Suganami T, Hachiya R, Shirakawa I, Kim-Saijo M, Tanaka M, Hamaguchi M, Takai-Igarashi T, Nakai M, Miyamoto Y, Ogawa Y.
|
| タイトル |
Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages.
|
| ジャーナル |
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.
|
| 巻・号 |
63(1)
|
| ページ |
152-61
|
| 公開日 |
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
|
| 引用数 |
42
|
|
WOS 分野
|
ENDOCRINOLOGY & METABOLISM
|
| リソース情報 |
| ヒト・動物細胞 |
RAW 264(RCB0535) |
