Differential and cell-type specific regulation of responses to Toll-like receptor agonists by ISO-1

Peter W. West, Lisa C. Parker, Jon R. Ward, Ian Sabroe

    Research output: Contribution to journalArticlepeer-review


    Macrophage migration inhibitory factor (MIF) plays vital roles in the regulation of responses to stimuli acting via Toll-like receptor (TLR)-4. Recently, a specific small molecule inhibitor of MIF (ISO-1) has been described. We investigated the effects of ISO-1 on TLR responses in primary human monocytes and monocyte-derived macrophages (MDM). In monocytes, ISO-1 caused marked suppression of TLR4-induced proinflammatory cytokine production, and to a lesser extent suppression of TLR2-induced responses. The lipopolysaccharide (LPS)-induced activation of cocultures of monocytes and endothelial cells was strongly inhibited by ISO-1. Suppression of monocyte TLR4 signalling by ISO-1 was associated with alterations in extracellular signal-related kinase (ERK)-1/2 activation status. Previously, regulation of TLR4 signalling by MIF has been noted to be through control of TLR4 expression, but we observed that the actions of ISO-1 were mediated without changes in cell surface TLR4 levels. In contrast, ISO-1 pretreatment did not inhibit responses of MDM to LPS. ISO-1 is a promising parent molecule which inhibits TLR-induced ERK activation and inflammatory cytokine production in monocytes, whose role may be complicated by cell-type specificity. © 2008 Blackwell Publishing Ltd.
    Original languageEnglish
    Pages (from-to)101-110
    Number of pages9
    Issue number1
    Publication statusPublished - Sept 2008


    • Atherosclerosis
    • Inflammation
    • LPS
    • MIF
    • Toll-like receptor


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