Abstract
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 language | English |
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Pages (from-to) | 101-110 |
Number of pages | 9 |
Journal | Immunology |
Volume | 125 |
Issue number | 1 |
DOIs | |
Publication status | Published - Sept 2008 |
Keywords
- Atherosclerosis
- Inflammation
- LPS
- MIF
- Toll-like receptor