title: Interleukin-1β induces hyaluronan and CD44-dependent cell protrusions that facilitate fibroblast-monocyte binding.
abstract: Persistent inflammation is a well-known determinant of progressive tissue fibrosis; however, the mechanisms underlying this process remain unclear. There is growing evidence indicating a role of the cytokine IL-1β in profibrotic responses. We previously demonstrated that fibroblasts stimulated with IL-1β increased their generation of the polysaccharide hyaluronan (HA) and increased their expression of the HA synthase enzyme (HAS-2). The aim of this study was to determine the significance of IL-1β-induced changes in HA and HAS-2 generation. In this study, we found that stimulation of fibroblasts with IL-1β results in the relocalization of HA associated with the cell to the outer cell membrane, where it forms HAS2- and CD44-dependent cell membrane protrusions. CD44 is concentrated within the membrane protrusions, where it co-localizes with the intracellular adhesion molecule 1. Furthermore, we have identified that these cell protrusions enhance IL-1β-dependent fibroblast-monocyte binding through MAPK/ERK signaling. Although previous data have indicated the importance of the HA-binding protein TSG-6 in maintaining the transforming growth factor β1-dependent HA coat, TSG-6 was not essential for the formation of the IL-1β-dependent HA protrusions, thus identifying it as a key difference between IL-1β- and transforming growth factor β1-dependent HA matrices. In summary, these data suggest that IL-1β-dependent HA generation plays a role in fibroblast immune activation, leading to sequestration of monocytes within inflamed tissue and providing a possible mechanism for perpetual inflammation.
authors.affiliation: Institute of Nephrology, Cardiff University, University Hospital of Wales, Heath Park, Cardiff, United Kingdom. merans@cf.ac.uk
authors.forename: Soma
authors.initials: S
authors.lastname: Meran
authors.forename: John
authors.initials: J
authors.lastname: Martin
authors.forename: Dong Dong
authors.initials: DD
authors.lastname: Luo
authors.forename: Robert
authors.initials: R
authors.lastname: Steadman
authors.forename: Aled
authors.initials: A
authors.lastname: Phillips
mesh_terms: D002448:Cell Adhesion / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology; D022081:Cell Surface Extensions / Q000276:immunology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000276:immunology* / Q000502:physiology; D014453:Glucuronosyltransferase / Q000276:immunology; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology*; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D009000:Monocytes / Q000276:immunology* / Q000502:physiology; D058628:Myofibroblasts / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000276:immunology
chemical_list: D015815:Cell Adhesion Molecules; D018960:Hyaluronan Receptors; D053583:Interleukin-1beta; C072273:TNFAIP6 protein, human; D053773:Transforming Growth Factor beta1; D018799:Intercellular Adhesion Molecule-1; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases