Cytokine-induced down-regulation of zfm1/splicing factor-1 promotes smooth muscle cell proliferation.
One hallmark of inflammation is the proliferation of bystander cells such as vascular smooth muscle cells (SMC), a process governed by growth factors and cytokines. Whereas cytokine induction of gene products promoting inflammation and proliferation is well characterized, little is known about the concomitant down-regulation of potentially counter-regulatory gene products in these cells. By employing the suppression subtractive hybridization-PCR technique, RNA isolated from rat aortic SMC treated with the cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) was subtracted from RNA of control cells. Eleven genes were identified, the expression of which fell by 44-77%. One, the transcriptional repressor splicing factor-1 or zfm1, was characterized further. Antisense oligonucleotide suppression of zfm1 protein synthesis mimicked the stimulatory effects of IL-1 beta and TNF alpha on SMC proliferation and expression of the chemokine MCP-1 and the vascular cell adhesion molecule-1. Moreover, in an in vivo mouse model of atherosclerosis, zfm1 abundance was decreased in proliferating arterial SMC. These findings suggest a role for zfm1 in controlling both proliferation and expression of pro-inflammatory gene products in SMC. Therefore, cytokine-induced down-regulation of zfm1 expression may contribute to the pathogenesis of hyperproliferative inflammatory diseases.
Cattaruzza
Marco
M
Department of Cardiovascular Physiology, University of Göttingen, Humboldtallee 23, 37073 Göttingen, Germany.
Schäfer
Katrin
K
Hecker
Markus
M
D000818:Animals; D001011:Aorta; D002352:Carrier Proteins / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007375:Interleukin-1 / Q000494:pharmacology; D007438:Introns; D007700:Kinetics; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D009687:Nuclear Proteins / Q000235:genetics*; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics*; D000072260:RNA Splicing Factors; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002352:Carrier Proteins; D016207:Cytokines; D017931:DNA Primers; D004268:DNA-Binding Proteins; D007375:Interleukin-1; D009687:Nuclear Proteins; D000072260:RNA Splicing Factors; C107467:SF1 protein, human; C491514:Sf1 protein, mouse; C491513:Sf1 protein, rat; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha