Interleukin-1β induces hyaluronan and CD44-dependent cell protrusions that facilitate fibroblast-monocyte binding

Am J Pathol. 2013 Jun;182(6):2223-40. doi: 10.1016/j.ajpath.2013.02.038. Epub 2013 Apr 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion / immunology
  • Cell Adhesion Molecules / immunology
  • Cell Differentiation / immunology
  • Cell Membrane / immunology
  • Cell Surface Extensions / immunology*
  • Cells, Cultured
  • Fibroblasts / immunology*
  • Fibroblasts / physiology
  • Glucuronosyltransferase / immunology
  • Humans
  • Hyaluronan Receptors / immunology*
  • Hyaluronan Synthases
  • Hyaluronic Acid / biosynthesis*
  • Intercellular Adhesion Molecule-1 / metabolism
  • Interleukin-1beta / immunology*
  • MAP Kinase Signaling System / immunology
  • Monocytes / immunology*
  • Monocytes / physiology
  • Myofibroblasts / immunology
  • Transforming Growth Factor beta1 / immunology


  • Cell Adhesion Molecules
  • Hyaluronan Receptors
  • Interleukin-1beta
  • TNFAIP6 protein, human
  • Transforming Growth Factor beta1
  • Intercellular Adhesion Molecule-1
  • Hyaluronic Acid
  • Glucuronosyltransferase
  • HAS2 protein, human
  • Hyaluronan Synthases