Differential and cell-type specific regulation of responses to Toll-like receptor agonists by ISO-1.
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.
West
Peter W
PW
Academic Unit of Respiratory Medicine, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK.
Parker
Lisa C
LC
Ward
Jon R
JR
Sabroe
Ian
I
D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D007555:Isoxazoles / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000276:immunology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists*; D014657:Vasculitis / Q000276:immunology
C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; C508606:CXCL8 protein, human; D016207:Cytokines; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D007555:Isoxazoles; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D048049:Extracellular Signal-Regulated MAP Kinases