title: Toll-like receptor 4-dependent activation of myeloid dendritic cells by leukocidin of Staphylococcus aureus.
abstract: Leukocidin (Luk), an exotoxin of Staphylococcus aureus consisting of LukF and LukS, is a hetero-oligomeric pore-forming cytolytic toxin toward human and rabbit polymorphonuclear leukocytes. However, it is uncertain how Luk affects the host immune response. In the present study, we investigated whether Luk has the ability to stimulate mouse bone marrow-derived myeloid dendritic cells (BM-DCs). LukF activated BM-DCs to generate IL-12p40 mRNA, induce intracellular expression and extracellular secretion of this cytokine and express CD40 on their surface, whereas LukS showed a much lower or marginal ability in the activation of BM-DCs than its counterpart component. Similarly, TNF-alpha was secreted by BM-DCs upon stimulation with these components. Combined addition of these components did not lead to a further increase in IL-12p40 secretion. IL-12p40 production caused by LukF was completely abrogated in BM-DCs from TLR4-deficient mice similarly to the response to lipopolysaccharide (LPS). Polymixin B did not affect the LukF-induced IL-12p40 production, although the same treatment completely inhibited the LPS-induced response. Boiling significantly inhibited the response caused by LukF, but not by LPS. Finally, in a luciferase reporter assay, LukF induced the activation of NF-kappaB in HEK293T cells transfected with TLR4, MD2 and CD14, whereas LukS did not show such activity. These results demonstrate that LukF caused the activation of BM-DCs by triggering a TLR4-dependent signaling pathway and suggests that Luk may affect the host inflammatory response as well as show a cytolytic effect on leukocytes.
authors.affiliation: Department of Infection Control and Laboratory Diagnostics, Internal Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai-shi, Miyagi 980-8575, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Inden
authors.forename: Jun
authors.initials: J
authors.lastname: Kaneko
authors.forename: Akiko
authors.initials: A
authors.lastname: Miyazato
authors.forename: Natsuo
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Shota
authors.initials: S
authors.lastname: Mouri
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shibuya
authors.forename: Kiwamu
authors.initials: K
authors.lastname: Nakamura
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Aoyagi
authors.forename: Masumitsu
authors.initials: M
authors.lastname: Hatta
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kunishima
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hirakata
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Itoh
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kaku
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kawakami
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology*; D019013:CD40 Antigens / Q000096:biosynthesis; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D007956:Leukocidins / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D019013:CD40 Antigens; D053762:Interleukin-12 Subunit p40; D007956:Leukocidins; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C108483:leukocidin S-component protein, Staphylococcus; C074300:LukF protein, Staphylococcus aureus