Histone deacetylase-1 is enriched at the platelet-derived growth factor-D promoter in response to interleukin-1beta and forms a cytokine-inducible gene-silencing complex with NF-kappab p65 and interferon regulatory factor-1.
Understanding the mechanisms governing cytokine control of growth factor expression in smooth muscle cells would provide invaluable insight into the molecular regulation of vascular phenotypes and create future opportunities for therapeutic intervention. Here, we report that the proinflammatory cytokine interleukin (IL)-1beta suppresses platelet-derived growth factor (PDGF)-D promoter activity and mRNA and protein expression in smooth muscle cells. NF-kappaB p65, induced by IL-1beta, interacts with a novel element in the PDGF-D promoter and inhibits PDGF-D transcription. Interferon regulatory factor-1 (IRF-1) is also induced by IL-1beta and binds to a different element upstream in the promoter. Immunoprecipitation and chromatin immunoprecipitation experiments showed that IL-1beta stimulates p65 interaction with IRF-1 and the accumulation of both factors at the PDGF-D promoter. Mutation of the IRF-1 and p65 DNA-binding elements relieved the promoter from IL-1beta-mediated repression. PDGF-D repression by IL-1beta involves histone deacetylation and interaction of HDAC-1 with IRF-1 and p65. HDAC-1 small interfering RNA ablates complex formation with IRF-1 and p65 and abrogates IRF-1 and p65 occupancy of the PDGF-D promoter. Thus, HDAC-1 is enriched at the PDGF-D promoter in cells exposed to IL-1beta and forms a cytokine-inducible gene-silencing complex with p65 and IRF-1.
Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052, Australia.
Mary Y
MY
Liu
Levon M
LM
Khachigian
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D050856:Interferon Regulatory Factor-1; D053583:Interleukin-1beta; D008222:Lymphokines; C427493:PDGFD protein, human; C498952:Pdgfd protein, rat; D010982:Platelet-Derived Growth Factor; D051996:Transcription Factor RelA; D056284:Histone Deacetylase 1