PMID- 37894865 OWN - NLM STAT- MEDLINE DCOM- 20231030 LR - 20231030 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 24 IP - 20 DP - 2023 Oct 14 TI - Endoplasmic Reticulum Stress Promotes the Expression of TNF-alpha in THP-1 Cells by Mechanisms Involving ROS/CHOP/HIF-1alpha and MAPK/NF-kappaB Pathways. LID - 10.3390/ijms242015186 [doi] LID - 15186 AB - Obesity and metabolic syndrome involve chronic low-grade inflammation called metabolic inflammation as well as metabolic derangements from increased endotoxin and free fatty acids. It is debated whether the endoplasmic reticulum (ER) stress in monocytic cells can contribute to amplify metabolic inflammation; if so, by which mechanism(s). To test this, metabolic stress was induced in THP-1 cells and primary human monocytes by treatments with lipopolysaccharide (LPS), palmitic acid (PA), or oleic acid (OA), in the presence or absence of the ER stressor thapsigargin (TG). Gene expression of tumor necrosis factor (TNF)-alpha and markers of ER/oxidative stress were determined by qRT-PCR, TNF-alpha protein by ELISA, reactive oxygen species (ROS) by DCFH-DA assay, hypoxia-inducible factor 1-alpha (HIF-1alpha), p38, extracellular signal-regulated kinase (ERK)-1,2, and nuclear factor kappa B (NF-kappaB) phosphorylation by immunoblotting, and insulin sensitivity by glucose-uptake assay. Regarding clinical analyses, adipose TNF-alpha was assessed using qRT-PCR/IHC and plasma TNF-alpha, high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), and oxidized low-density lipoprotein (OX-LDL) via ELISA. We found that the cooperative interaction between metabolic and ER stresses promoted TNF-alpha, ROS, CCAAT-enhancer-binding protein homologous protein (CHOP), activating transcription factor 6 (ATF6), superoxide dismutase 2 (SOD2), and nuclear factor erythroid 2-related factor 2 (NRF2) expression (p