title: Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages.
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.
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yorihiro
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suganami
authors.forename: Rumi
authors.initials: R
authors.lastname: Hachiya
authors.forename: Ibuki
authors.initials: I
authors.lastname: Shirakawa
authors.forename: Misa
authors.initials: M
authors.lastname: Kim-Saijo
authors.forename: Miyako
authors.initials: M
authors.lastname: Tanaka
authors.forename: Miho
authors.initials: M
authors.lastname: Hamaguchi
authors.forename: Takako
authors.initials: T
authors.lastname: Takai-Igarashi
authors.forename: Michikazu
authors.initials: M
authors.lastname: Nakai
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D057895:Haploinsufficiency; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D015850:Interleukin-6; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D051701:Activating Transcription Factor 4; D019892:eIF-2 Kinase