P53 OVEREXPRESSION AND DOWN-REGULATION OF INTER-ALPHA-INHIBITOR ARE ASSOCIATED WITH HYALURONIDASE ENHANCEMENT OF TNF CYTOTOXICITY IN L929 FIBROBLASTS

Degradation of extracellular matrix by hyaluronidase increases murine L929 cell sensitivity to tumor necrosis factor (TNF) cytotoxicity. See ding and culturing L929 cells onto the matrix of serum fetuin and the hyaluronate-binding inter-alpha-inhibitor resulted in inhibition of hy aluronidase-enhanced TNF killing, suggesting that the release of these proteins from hyaluronidase-degraded matrix confers cellular TNF susc eptibility. Metabolic labeling studies showed that hyaluronidase media ted de novo protein synthesis and downregulated several proteins in L9 29 cells. Specifically, hyaluronidase upregulated p53 protein expressi on (>200%) but downregulated a p85 inter-alpha-inhibitor-like protein (>90%) in L929 cells, whereas it had no effect on the protein levels o f ICH-1, Bcl-xL, Bcl-2, Fas ligand, CAS (cellular apoptosis susceptibl e protein), TIAR (an RNA-binding protein) and alpha-tubulin. Conceivab ly, hyaluronidase enhancement of TNF sensitivity in L929 cells is p53- dependent and the matrix inter-alpha-inhibitor contributes a protectiv e role against TNF cytotoxicity. (C) 1998 Elsevier Science Ireland Ltd . All rights reserved.