ANTITHETIC ACTION OF HYALURONAN 6-MER IN UNDIFFERENTIATED AND DIFFERENTIATED SH-SY5Y CELLS

Small hyaluronan (HA) fragments are able to induce inflammation by stimulating both CD44 and toll-like receptor 4 (TLR-4). CD44 and TLR-4 stimulation activates NF-kB nuclear translocation that in turn induces pro-inflammatory intermediates production . Up-regulation of CD44 and TLR-4 was also reported during neuronal inflammation in course of Alzheimer disease as well as in Dementia with Lewy bodies. Although the pro- inflammatory effect of HA small oligosaccharides has been reported in several cell lines such as fibroblasts, chondrocytes and synoviocytes, little is known about such effect in neuronal cells. The aim of this study was to investigate the effects of small HA oligosaccharides (HA 6-mers) treatment on both undifferentiated ,human neuroblastoma, and differentiated, neuron-like, SH-SY5Y cells. Messenger-RNA levels for TLR-2, TLR-4, CD44, TNF-alpha, iNOS as well as synphilin-1 and alpha- synuclein, both specific markers of Parkinson’s disease, were measured by PCR Real Time in 6-mer HA treated and untreated SH-SY5Y cell cultures . The results obtained showed an antithetic function of HA 6-mer in relation to the type of cells receiving the treatment . HA 6-mer treatment produced a down-regulation of all investigated parameters in undifferentiated SH-SY5Y cells, while it produced an up-regulation of the same parameters in differentiated SH-SY5Y cells, which is in line with the well-known pro inflammatory effect of HA 6-mer . Therefore, these data, suggest that HA 6-mer treatment could exhibit two antithetic modulatory effects: a) The known stimulatory effect on TLR-2, TLR-4 and CD44 receptors followed by inflammatory intermediates activation via NF-kB, in differentiated SH-SY5Y cells. b) A singular down-regulation of all above listed parameters, suggesting a regulatory mechanism by the cancerous cell in attempt to reduce any onset of the inflammatory cascade. The mechanism of such anti-inflammatory response induced by HA 6-mer in undifferentiated SH-SY5Y cells will be further investigated.