title: Cucurbitacin D is a new inflammasome activator in macrophages.
abstract: We previously reported that cucurbitacin D isolated from Trichosanthes kirilowii has anti-tumor roles to leukemia cells. However, the effect of cucurbitacin D on immune cells is not fully understood although there is no toxic activity to normal cells. In this study, immunomodulating activities of cucurbitacin D were investigated in macrophages. Cucurbitacin D could increase LPS-induced interleukin (IL)-1β production in culture supernatant of THP-1 cells, peritoneal exudate cells (PECs), bone marrow derived macrophages (BMDMs), and RAW264 cells. At the transcriptional level, cucurbitacin D enhanced LPS-induced IL-1β mRNA expression through activation of ERK1/2 mitogen-activated protein kinases (MAPKs). At the posttranscriptional level, the activation of caspase-1 induced by cucurbitacin D has also been demonstrated following treatment with a caspase-1 inhibitor and siRNA. Importantly, cucurbitacin D has further been shown to induce inflammasome activation independent of ERK1/2 activation. Western blotting showed interaction of NOD-like receptor family, pyrin domain containing 3 (NALP3) and apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain (ASC), suggesting activation of the inflammasome and a possible reason for activation of caspase-1. Taken together, these results suggest that cucurbitacin D could initiate immunomodulating activity in macrophages to lead to inflammasome activation as well as enhancement of LPS signaling.
authors.affiliation: Department of Immunology and Parasitology, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Song
authors.forename: Ning
authors.initials: N
authors.lastname: Ding
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Kanazawa
authors.forename: Uki
authors.initials: U
authors.lastname: Yamashita
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D002478:Cells, Cultured; D007155:Immunologic Factors / Q000494:pharmacology*; D058847:Inflammasomes / Q000187:drug effects / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D007155:Immunologic Factors; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014315:Triterpenes; C038105:cucurbitacin D; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: ASC; BMDMs; Cucurbitacin D; ERK1/2; IL-1β; Inflammasome; LDH; MAPKs; Macrophages; NALP3; NOD-like receptor family, pyrin domain containing 3; PECs; THMs; TLR; Toll-like receptor; apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain; bone marrow derived macrophages; lactate dehydrogenase; mitogen-activated protein kinases; peritoneal exudate cells; traditional medicinal herbs