title: TLR-mediated secretion of endoplasmic reticulum aminopeptidase 1 from macrophages.
abstract: Macrophages play an important role in host defense under several immunological, inflammatory, and/or infectious conditions. In our previous work, we demonstrated that endoplasmic reticulum aminopeptidase 1 (ERAP1) was secreted from macrophages in response to LPS and IFN-γ, and it enhanced their phagocytic activity. In this study, we analyzed the mechanism of LPS/IFN-γ-induced ERAP1 secretion. LPS/IFN-γ-induced secretion of the enzyme from the murine macrophage cell line RAW264.7 was suppressed by polymyxin B. Several agonists of TLRs, such as Pam3CSK4, FSL-1, and ODN1826, induced its secretion. In contrast, neutralizing Abs to IFN-β and TNF-α receptor type 1 suppressed its secretion. Using murine peritoneal macrophages derived from TNF-α and type 1 IFNR knockout mice, we confirmed the involvement of these two cytokines in ERAP1 secretion. In addition, secretion of ERAP1 from both RAW264.7 cells and murine peritoneal macrophages was induced by A23187 and thapsigargin and inhibited by BAPTA-AM and the calmodulin inhibitor W7. These results suggest that LPS/IFN-γ-induced secretion of ERAP1 is mediated by TLRs via induction of intermediate cytokines such as IFN-β and TNF-α, which in turn lead to enhanced cytosolic Ca(2+) levels and calmodulin activation.
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo-Heisei University, Nakano, Tokyo 164-8530, Japan;
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Goto
authors.forename: Kenji
authors.initials: K
authors.lastname: Ogawa
authors.forename: Takahiro J
authors.initials: TJ
authors.lastname: Nakamura
authors.forename: Akira
authors.initials: A
authors.lastname: Hattori
authors.forename: Masafumi
authors.initials: M
authors.lastname: Tsujimoto
mesh_terms: D000626:Aminopeptidases / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D015778:Minor Histocompatibility Antigens; D051193:Toll-Like Receptors; D000626:Aminopeptidases; C509944:ERAP1 protein, mouse