Interferon regulatory factor 1 is an essential and direct transcriptional activator for interferon {gamma}-induced RANTES/CCl5 expression in macrophages.
Interferon regulatory factor 1 (IRF-1) is an important transcription factor in interferon gamma (IFNgamma)-mediated signaling in the development and function of NK cells and cytotoxic T lymphocytes. RANTES (regulated on activation normal T cell expressed and secreted; CCL5) is a member of the CC chemokine family of proteins, which is strongly chemoattractant for several important immune cell types in host defense against infectious agents and cancer. However, the role of IFNgamma and IRF-1 in the regulation of RANTES gene expression and their operative mechanisms in macrophages have not been established. We report here that RANTES expression in IRF-1-null mice, primarily in macrophages, in response to carcinogenic stimulation in vivo and in vitro and to IFNgamma but not to lipopolysaccharide in vitro, was markedly decreased. As a result, RANTES-mediated chemoattraction of CCR5(+) target cells was also severely impaired. Adenovirus-mediated gene transduction of IRF-1 in primary macrophages resulted in enhanced RANTES expression. The IFNgamma and IRF1 response element was localized to a TTTTC motif at -147 to -143 of the mouse RANTES promoter, to which endogenous or recombinant IRF-1 can physically bind in vitro and in vivo. This study uncovers a novel IFNgamma-induced pathway in RANTES expression mediated by IRF-1 in macrophages and elucidates an important host defense mechanism against neoplastic transformation.
Liu
Jianguo
J
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021, USA.
Guan
Xiuqin
X
Ma
Xiaojing
X
D000256:Adenoviridae / Q000235:genetics; D020816:Amino Acid Motifs; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D015704:CD4 Antigens / Q000096:biosynthesis; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D018946:Chemokine CCL5 / Q000378:metabolism*; D019742:Chemokines, CC / Q000378:metabolism*; D002633:Chemotaxis; D047369:Chromatin Immunoprecipitation; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection
C483024:CCL5 protein, human; D015704:CD4 Antigens; D018946:Chemokine CCL5; D019742:Chemokines, CC; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D008070:Lipopolysaccharides; D010750:Phosphoproteins; D012333:RNA, Messenger; D007371:Interferon-gamma; D012260:Ribonucleases