Extracellular Hsp70 inhibits pro-inflammatory cytokine production by IL-10 driven down-regulation of C/EBPβ and C/EBPδ

AbstractPurpose: 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 facto...