Lipopolysaccharide induces formyl peptide receptor 1 gene expression in macrophages and neutrophils via transcriptional and posttranscriptional mechanisms.
Bacterial infection promotes the infiltration of inflammatory leukocytes mediated in part by receptors for formyl-methionine-terminated peptides. In this study, we show that LPS can markedly enhance the expression of the formyl peptide receptor gene (FPR1) in mouse macrophages and neutrophils by enhancing transcription and by stabilization of the mRNA. In untreated cells, FPR1 mRNA exhibits a half-life of approximately 90 min and this is markedly increased (to >6 h) following stimulation with LPS. Although FPR1 mRNA levels remained elevated over baseline for >20 h after stimulation, the half-life of the message is prolonged only transiently. LPS-induced FPR1 mRNA expression is mediated in part by the intermediate production of secreted factors. First, the response to LPS is partially blocked by the translational inhibitor cycloheximide. Second, a heat-labile but polymyxin B-insensitive factor present in supernatants from LPS-treated cells stimulates enhanced expression of FPR1 mRNA and, like LPS, promotes stabilization of FPR1 mRNA. Furthermore, supernatants from LPS-treated wild-type macrophages can stimulate FPR1 mRNA expression in LPS-insensitive macrophages from TLR4-mutant mice. Elevated FPR1 mRNA expression is also induced in response to ligands for TLR2 and TLR3. TNF-alpha but not IL-1, IL-6, IFN-beta, and IFN-gamma can mimic the effects of LPS although other factors apparently also contribute. Collectively, these findings define a distinct molecular pattern of response to TLR stimulation in inflammatory phagocytes and demonstrate that regulation of FPR1 expression is achieved through both transcriptional and posttranscriptional mechanisms.
Mandal
Palash
P
Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Novotny
Michael
M
Hamilton
Thomas A
TA
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger / Q000032:analysis; D044042:Receptors, Formyl Peptide / Q000235:genetics*; D011971:Receptors, Immunologic / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects*
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C469988:Fpr1 protein, mouse; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4