title: ER stress induced impaired TLR signaling and macrophage differentiation of human monocytes.
abstract: Endoplasmic reticulum (ER) stress causes impairment of the intracellular protein synthesis machinery, affecting various organ functions and homeostasis systems, including immunity. We found that ER stress induced by the N-linked glycosylation inhibitor, tunicamycin, caused susceptibility to apoptosis in the human monocytic cell line, THP-1 cells. Importantly, prior to tunicamycin-induced apoptosis, the proinflammatory response to toll-like receptor (TLR) 4 ligand lipopolysaccharide (LPS) stimulation was attenuated with respect to the expression of the proinflammatory cytokines. This impaired expression of proinflammatory cytokines was a consequence of the inhibition of NF-κB activation. Moreover, tunicamycin-induced ER stress disturbed the differentiation of THP-1 cells into macrophages induced by phorbol-12-myristate-13-acetate treatment. We also confirmed that ER stress affected the response of primary human monocytes to TLR ligand and their ability to differentiate into macrophages. These data suggest that ER stress imposes an important pathological insult to the immune system, affecting the crucial functions of monocytes.
authors.affiliation: Disease Control and Homeostasis, Kanazawa University, 13-1, Takaramachi, Kanazawa 920-8641, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Komura
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Sakai
authors.forename: Masao
authors.initials: M
authors.lastname: Honda
authors.forename: Toshinari
authors.initials: T
authors.lastname: Takamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Wada
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000276:immunology*; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D018613:Microscopy, Confocal; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D014415:Tunicamycin