Mechanisms of hyaluronan-induced up-regulation of ICAM-1 and VCAM-1 expression by murine kidney tubular epithelial cells: hyaluronan triggers cell adhesion molecule expression through a mechanism involving activation of nuclear factor-kappa B and activating protein-1.
The matrix constituent hyaluronan (HA) markedly accumulates in inflammatory lesions. To gain insight into the biologic significance of this phenomenon we tested the hypothesis that HA could regulate cell adhesion molecule expression in epithelial cells. Using a clonal line of mouse cortical tubular (MCT) cells we found that fragmented intermediate m.w., but not high m.w., HA markedly increased ICAM-1 and VCAM-1 steady state mRNA and cell surface expression. Up-regulation of ICAM-1 and VCAM-1 mRNA by HA was preceded by a marked increase in NF-kappaB and activating protein-1 DNA binding activity in MCT cells. Transcript levels for the NF-kappaB inhibitor IkappaBalpha and for the activating protein-1 constituents c-jun and c-fos also increased in response to HA stimulation of tubular cells. Inhibition of NF-kappaB with the serine protease inhibitor N-tosyl-L-phenylalanine chloromethyl ketone blocked the HA-mediated expression of ICAM-1 and VCAM-1 in MCT cells. In conclusion, HA displays proinflammatory effects by directly stimulating the expression of the cell adhesion molecules ICAM-1 and VCAM-1 in mouse kidney epithelial cells. HA could thereby play an important role in leukocyte adhesion in inflammatory renal diseases.
Oertli
B
B
Physiological Institute, University of Zurich-Irchel, Switzerland.
Beck-Schimmer
B
B
Fan
X
X
Wüthrich
R P
RP
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D004727:Endothelium; D004847:Epithelial Cells / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000187:drug effects; D007672:Kidney Cortex; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism*; D008168:Lung; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects* / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000187:drug effects
D016328:NF-kappa B; D018808:Transcription Factor AP-1; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D006820:Hyaluronic Acid