SUPPRESSION OF SYNDECAN-1 EXPRESSION TUMOR-NECROSIS-FACTOR-ALPHA

Syndecan-1 is a cell surface proteoglycan that binds extracellular mat rix components and modulates the activity of heparin-binding growth fa ctors, The expression of syndecan-1 is modified during development, ca rcinogenesis, and tissue regeneration, During cutaneous wound healing, syndecan-1 expression is transiently induced in newly-formed capillar ies of granulation tissue as well as in proliferating keratinocytes, T o study the mechanisms underlying this regulation we investigated the effects of several growth factors/cytokines on syndecan-1 expression i n two human cell lines: EA.hy 926 endothelial cells and HaCaT keratino cytes. None of these factors significantly altered syndecan-1 mRNA exp ression in cultured keratinocytes, but when given to endothelial cells , tumor necrosis factor-alpha (TNF-alpha) specifically and dose-depend ently suppressed syndecan-1 expression at both mRNA and protein levels , TNF-alpha reduced the amount of syndecan-1 protein in EA.hy 926 cell s in both the presence and absence of serum and, at the same time, ind uced the expression of intercellular adhesion molecule-1 (ICAM-1). The suppressive effect of TNF-alpha on endothelial syndecan-1 expression was reproducible in in vivo experiments in which TNF-alpha coated bead s were administered directly to healing skin wounds of mice. Data supp orting these findings were further obtained by injecting TNF-alpha int o an experimental rat granulation tissue model, In this tissue TNF a s uppressed syndecan-1 mRNA expression by approximately 80%. These resul ts indicate that TNF-alpha is capable of down-regulating syndecan-1 ex pression in endothelial cells both in vitro and in vivo and suggest th at similar mechanisms may be responsible for the changes in syndecan-1 expression observed during various regenerative, developmental, and m alignant processes.