Renal proximal tubular epithelial cell transforming growth factor-beta1 generation and monocyte binding

Am J Pathol. 2004 Sep;165(3):763-73. doi: 10.1016/s0002-9440(10)63339-1.

Abstract

With increasing awareness of the importance of renal cortical interstitial fibrosis, interest has focused on the mechanisms that stimulate generation of profibrotic factors including transforming growth factor (TGF)-beta1, by resident cells, such as proximal tubular epithelial cells (PTCs). Infiltration of monocytes, has been implicated in the pathogenesis of a wide variety of renal diseases, however, how interaction between monocytes and PTCs may affect the generation of TGF-beta1 by the resident cell is unknown. We demonstrate that monocytes stimulate TGF-beta1 transcription and protein synthesis by PTCs. This was dependent on direct cell contact and TGF-beta1 transcriptional activation that was dependent on ICAM-1 binding of unstimulated monocytes. This was mimicked by antibody cross-linking of PTC surface ICAM-1. We have previously identified hyaluronan (HA)-based structures on the surface of PTCs, both primary cultures and the HK-2 cell line. Removal of cell-surface HA increased ICAM-1-dependent monocyte binding and stimulation of TGF-beta1 synthesis. Furthermore, we demonstrate that binding of monocytes to HA-based structures on the cell surface of HK-2 cells interferes with this response. In summary, we have demonstrated that HA-based pericellular structures down-regulate proinflammatory and profibrotic responses by modulation of monocyte-driven ICAM-1-dependent cell activation and TGF-beta1 generation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Communication
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Humans
  • Hyaluronic Acid / metabolism
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Kidney Tubules, Proximal / metabolism*
  • Luciferases / metabolism
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Monocytes / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • Transcription, Genetic
  • Transforming Growth Factor beta / biosynthesis*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta1
  • U937 Cells

Substances

  • TGFB1 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Intercellular Adhesion Molecule-1
  • Hyaluronic Acid
  • Luciferases