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 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.

ATF6 Mediates a Pro-Inflammatory Synergy Between ER Stress and TLR Activation in the Pathogenesis of Liver Ischemia-Reperfusion Injury

“…Systemic biology studies of ER stressed cells have resulted in the identification of a novel NLRP3 inflammasome activation pathway mediated by IRE1 α (upstream of XBP1), which promoted β cell death in diabetes (38, 39). Although the direct connection of ATF4 to inflammatory innate immune activation has yet to be established, a recent study revealed its involvement in saturated fatty acid induced IL-6 production in macrophages (40). Although CHOP downstream of ATF4 has been firmly linked to ER stress-induced cell death, it has been shown to regulate IL-23 expression in ER stressed dendritic cells (41).…”

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

“…ATF4 was also shown to contribute to LPS-induced C-C motif ligand 2 (CCL2) production in endothelial cells and retina and IL6 in macrophages (Iwasaki et al 2014, Huang et al 2015. Furthermore, XBP1s is implicated in synergistic production of type 1 interferons (IFNs), for example, IFN-β or IFN-α, in response to combination of ER stress and Toll-like receptor (TLR) signaling in macrophages (Martinon et al 2010, Zeng et al 2010.…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…ATF4 is also implicated in the saturated fatty acid (SFA)-induced IL-6 expression in macrophages (Iwasaki et al 2014). Attenuation of ATF4 in macrophages markedly inhibits SFA-induced IL-6 expression, whereas forced expression of ATF4 enhances IL-6 expression through direct activation of the IL-6 promoter and/or activation of NF-κB (Iwasaki et al 2014).…”