title: Toll-like receptor (TLR)2 and TLR4 agonists regulate CCR expression in human monocytic cells.
abstract: Interactions between proinflammatory and cell maturation signals, and the pathways that regulate leukocyte migration, are of fundamental importance in controlling trafficking and recruitment of leukocytes during the processes of innate and adaptive immunity. We have investigated the molecular mechanisms by which selective Toll-like receptor (TLR)2 and TLR4 agonists regulate expression of CCR1 and CCR2 on primary human monocytes and THP-1 cells, a human monocytic cell line. We found that activation of either TLR2 (by Pam(3)CysSerLys(4)) or TLR4 (by purified LPS) resulted in down-modulation of both CCR1 and CCR2. Further investigation of TLR-induced down-modulation of CCR1 revealed differences in the signaling pathways activated, and chemokines generated, via the two TLR agonists. TLR2 activation caused slower induction of the NF-kappa B and mitogen-activated protein kinase signaling pathways and yet a much enhanced and prolonged macrophage-inflammatory protein 1 alpha (CC chemokine ligand 3) protein production, when compared with TLR4 stimulation. Enhanced macrophage-inflammatory protein 1 alpha production may contribute to the prolonged down-regulation of CCR1 cell surface expression observed in response to the TLR2 agonist, as preventing chemokine generation with the protein synthesis inhibitor cycloheximide, or CCR1 signaling with the receptor antagonist UCB35625, abolished TLR2- and TLR4-induced CCR1 down-modulation. This result suggests an autocrine pathway, whereby TLR activation can induce chemokine production, which then leads to homologous down-regulation of the cognate receptors. This work provides further insights into the mechanisms that regulate leukocyte recruitment and trafficking during TLR-induced inflammatory responses.
authors.affiliation: Section of Functional Genomics, Division of Genomic Medicine, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Parker
authors.forename: Moira K B
authors.initials: MK
authors.lastname: Whyte
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
authors.forename: Steven K
authors.initials: SK
authors.lastname: Dower
authors.forename: Ian
authors.initials: I
authors.lastname: Sabroe
mesh_terms: D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008070:Lipopolysaccharides / Q000302:isolation & purification / Q000494:pharmacology; D008074:Lipoproteins / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: C515300:CCR1 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D016207:Cytokines; D008070:Lipopolysaccharides; D008074:Lipoproteins; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C061108:N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine; D003513:Cycloheximide