PURPOSE: Extracellular Hsp70 has anti-inflammatory potential, demonstrated in different models of inflammatory diseases. We investigated probable mechanisms used by Hsp70 to down-regulate pro-inflammatory cytokines. MATERIALS AND METHODS: We analysed cytokine mRNA levels in bone marrow-derived murine dendritic cells treated with Hsp70, lipopolysaccharide (LPS) and peptidoglycan (PGN) or OVA (an irrelevant protein control), hypothesising that this was mediated by C/EBPβ and C/EBPδ transcription factors. We also tested the involvement of TLR2, IL-10, ERK and STAT3, using genetically deficient mice and pharmacological inhibitors. RESULTS: C/EBPβ and C/EBPδ levels were inhibited in bone marrow derived dendritic cells (BMDCs) treated with Hsp70, and that correlated with inhibition of TNF-α, IFN-γ and MCP-1. Such inhibition was not observed in TLR2 or IL-10 knockout mice, and was also abrogated upon pretreatment of cells with ERK and JAK2/STAT3 inhibitors. CONCLUSIONS: C/EBPβ and C/EBPδ transcription factors are inhibited by Hsp70 treatment, and their inhibition occurs via the TLR2-ERK-STAT3-IL-10 pathway in BMDCs, mediating the anti-inflammatory effects of Hsp70.
PURPOSE: Extracellular Hsp70 has anti-inflammatory potential, demonstrated in different models of inflammatory diseases. We investigated probable mechanisms used by Hsp70 to down-regulate pro-inflammatory cytokines. MATERIALS AND METHODS: We analysed cytokine mRNA levels in bone marrow-derived murine dendritic cells treated with Hsp70, lipopolysaccharide (LPS) and peptidoglycan (PGN) or OVA (an irrelevant protein control), hypothesising that this was mediated by C/EBPβ and C/EBPδ transcription factors. We also tested the involvement of TLR2, IL-10, ERK and STAT3, using genetically deficient mice and pharmacological inhibitors. RESULTS: C/EBPβ and C/EBPδ levels were inhibited in bone marrow derived dendritic cells (BMDCs) treated with Hsp70, and that correlated with inhibition of TNF-α, IFN-γ and MCP-1. Such inhibition was not observed in TLR2 or IL-10 knockout mice, and was also abrogated upon pretreatment of cells with ERK and JAK2/STAT3 inhibitors. CONCLUSIONS: C/EBPβ and C/EBPδ transcription factors are inhibited by Hsp70 treatment, and their inhibition occurs via the TLR2-ERK-STAT3-IL-10 pathway in BMDCs, mediating the anti-inflammatory effects of Hsp70.
Authors: Lucas Tirloni; José Reck; Renata Maria Soares Terra; João Ricardo Martins; Albert Mulenga; Nicholas E Sherman; Jay W Fox; John R Yates; Carlos Termignoni; Antônio F M Pinto; Itabajara da Silva Vaz Journal: PLoS One Date: 2014-04-24 Impact factor: 3.240
Authors: Ana Cristina Gomes-Santos; Rafael Pires de Oliveira; Thaís Garcias Moreira; Archimedes Barbosa Castro-Junior; Bernardo Coelho Horta; Luísa Lemos; Leonardo Augusto de Almeida; Rafael Machado Rezende; Denise Carmona Cara; Sérgio Costa Oliveira; Vasco Ariston Carvalho Azevedo; Anderson Miyoshi; Ana Maria Caetano Faria Journal: Front Immunol Date: 2017-01-30 Impact factor: 7.561