title: Interleukin-1beta induces increased transcriptional activation of the transforming growth factor-beta-activating integrin subunit beta8 through altering chromatin architecture.
abstract: The integrin αvβ8 is a cell surface receptor for the latent domain (LAP) of the multifunctional cytokine TGF-β. Through its association with LAP, TGF-β is maintained in a latent form that must be activated to function. Binding to the integrin αvβ8 with subsequent metalloproteolytic cleavage of LAP represents a major mechanism of TGF-β activation in vivo. Altered expression of the integrin β8 subunit (ITGB8) is found in human chronic obstructive pulmonary disease, cancers, and brain vascular malformations. We have previously shown that the proinflammatory cytokine interleukin-1β (IL-1β) increases ITGB8 expression on lung fibroblasts, which increases αvβ8-mediated TGF-β activation in fibrosis and pathologic inflammation. Here we report the mechanism of increased ITGB8 expression by IL-1β. Our data support a model where the chromatin architecture of the ITGB8 core promoter is altered by nucleosomal repositioning that enhances the interaction of an AP1 complex (containing c-Jun and ATF2). This repositioning is caused by the dissociation of HDAC2 with the ITGB8 core promoter, leading to increased histone H4 acetylation and a loosening of nucleosomal-DNA interactions allowing "opening" of the chromatin structure and increased association of c-Jun and ATF-2. These changes are mediated through NFκB- and p38-dependent pathways. Ultimately, these events culminate in increasing ITGB8 transcription, αvβ8 surface expression, and αvβ8-mediated TGFβ activation.
authors: Department Pathology, School of Medicine, University of California, San Francisco, California 94110, USA.
authors: Jennifer A
authors: JA
authors: Markovics
authors: Jun
authors: J
authors: Araya
authors: Stephanie
authors: S
authors: Cambier
authors: Sangeeta
authors: S
authors: Somanath
authors: Stephanie
authors: S
authors: Gline
authors: David
authors: D
authors: Jablons
authors: Arthur
authors: A
authors: Hill
authors: Paul J
authors: PJ
authors: Wolters
authors: Stephen L
authors: SL
authors: Nishimura
mesh_terms: D000107:Acetylation; D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D004247:DNA / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D039482:Integrin alpha5 / Q000096:biosynthesis / Q000235:genetics; D039641:Integrin beta Chains / Q000096:biosynthesis* / Q000235:genetics; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D002843:Chromatin; D006657:Histones; C508585:IL1B protein, human; D039482:Integrin alpha5; D039641:Integrin beta Chains; D053583:Interleukin-1beta; D016328:NF-kappa B; D009707:Nucleosomes; D016755:Proto-Oncogene Proteins c-jun; D016212:Transforming Growth Factor beta; D004247:DNA; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2