title: Modulation of murine macrophage TLR7/8-mediated cytokine expression by mesenchymal stem cell-conditioned medium.
abstract: Increasing evidence suggests that mesenchymal stem cells (MSCs) play anti-inflammatory roles during innate immune responses. However, little is known about the effect of MSCs or their secretions on the ligand response of Toll-like receptor (TLR) 7 and TLR8, receptors that recognize viral single-stranded RNA (ssRNA). Macrophages play a critical role in the innate immune response to ssRNA virus infection; therefore, we investigated the effect of MSC-conditioned medium on cytokine expression in macrophages following stimulation with TLR7/8 ligands. After stimulation with TLR7/8 ligand, bone marrow-derived macrophages cultured with MSCs or in MSC-conditioned medium expressed lower levels of tumor necrosis factor (TNF) α and interleukin (IL) 6 and higher levels of IL-10 compared to macrophages cultured without MSCs or in control medium, respectively. The modulations of cytokine expression were associated with prostaglandin E2 (PGE2) secreted by the MSCs. PGE2 enhanced extracellular signal-related kinase (ERK) signaling and suppressed nuclear factor- κ B (NF- κ B) signaling. Enhanced ERK signaling contributed to enhanced IL-10 production, and suppression of NF- κ B signaling contributed to the low production of TNF- α . Collectively, these results indicate that MSCs and MSC-conditioned medium modulate the cytokine expression profile in macrophages following TLR7/8-mediated stimulation, which suggests that MSCs play an immunomodulatory role during ssRNA virus infection.
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Asami
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishii
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.forename: Ho
authors.initials: H
authors.lastname: Namkoong
authors.forename: Sadatomo
authors.initials: S
authors.lastname: Tasaka
authors.forename: Kenichi
authors.initials: K
authors.lastname: Matsushita
authors.forename: Ken
authors.initials: K
authors.lastname: Ishii
authors.forename: Kazuma
authors.initials: K
authors.lastname: Yagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Yohei
authors.initials: Y
authors.lastname: Funatsu
authors.forename: Naoki
authors.initials: N
authors.lastname: Hasegawa
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D017077:Culture Media, Conditioned / Q000737:chemistry*; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D012328:RNA Viruses; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D007155:Immunologic Factors; D015850:Interleukin-6; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C498144:Rela protein, mouse; C552579:TLR8 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases