title: Interferon regulatory factor-2 is a transcriptional activator in muscle where It regulates expression of vascular cell adhesion molecule-1.
abstract: Previously, we have suggested that vascular cell adhesion molecule-1 (VCAM-1) and its integrin receptor alpha4beta1 mediate cell-cell interactions important for skeletal myogenesis. Expression of the receptors subsequently subsides in muscle after birth. Here, we examine the mechanism regulating VCAM-1 gene expression in muscle. An enhancer located between the TATA box and the transcriptional start site is responsible for VCAM-1 gene expression in muscle-this element is inactive in endothelial cells where VCAM-1 expression is dependent on nuclear factor kappaB sites and inflammatory cytokines. We identify interferon regulatory factor-2 (IRF-2), a member of the interferon regulatory factor family, as the enhancer-binding transcription factor and show that expression of IRF-2 parallels that of VCAM-1 during mouse skeletal myogenesis. IRF-2 is not dependent upon cytokines for expression or activity, and it has been shown to act as a repressor in other nonmuscle cell types. We show that the basic repressor motif located near the COOH-terminal of IRF-2 is not active in muscle cells, but instead an acidic region in the center of the molecule functions as a transactivating domain. Although IRF-2 and VCAM-1 expression diminishes on adult muscle fiber, they are retained on myogenic stem cells (satellite cells). These satellite cells proliferate and fuse to regenerate muscle fiber after injury or disease. We present evidence that VCAM-1 on satellite cells mediates their interaction with alpha4beta1(+) leukocytes that invade the muscle after injury or disease. We propose that VCAM-1 on endothelium generally recruits leukocytes to muscle after injury, whereas subsequent interaction with VCAM-1 on regenerating muscle cells focuses the invading leukocytes specifically to the sites of regeneration.
authors.affiliation: Department of Medicine and Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Jesse
authors.forename: R
authors.initials: R
authors.lastname: LaChance
authors.forename: M F
authors.initials: MF
authors.lastname: Iademarco
authors.forename: D C
authors.initials: DC
authors.lastname: Dean
mesh_terms: D000818:Animals; D002450:Cell Communication; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D015536:Down-Regulation; D016189:Dystrophin / Q000378:metabolism; D005786:Gene Expression Regulation; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism; D050836:Interferon Regulatory Factor-2; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D012038:Regeneration; D012097:Repressor Proteins; D013234:Stem Cells; D016385:TATA Box; D015534:Trans-Activators; D014157:Transcription Factors; D015533:Transcriptional Activation; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D016189:Dystrophin; D039041:Integrin alpha4beta1; D016023:Integrins; D050836:Interferon Regulatory Factor-2; C494230:Irf2 protein, mouse; D016201:Receptors, Lymphocyte Homing; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1