Hyaluronan oligosaccharides modulate inflammatory response, NIS and thyreoglobulin expression in human thyrocytes

Autoimmune thyroid diseases, such as Hashimoto's thyroiditis, are characterized by lymphocytic infiltration and altered function of the thyroid. During inflammation, it has been reported a decreased expression in Tg and NIS, accompanied by an increase in HA production that accumulates in the gland. HA fragments produced in different pathological states can modulate gene expression in a variety of cell types and may prime inflammatory response by interacting with the TLR-2, TLR-4 and CD44 that, in turn, induce NF-kB activation finally responsible of inflammatory mediator transcription, such as IL-1 beta, TNF-alpha and IL-6. The aim of this study was to investigate the potential inflammatory effect and the biochemical pathways activated by 6-mer HA oligosaccharides in cultured human thyrocytes. 6-mer HA treatment induced upregulation of TLR-2, TLR-4, CD44 mRNA and related protein levels, increased HA production and NF-kB activation, that in turn increased IL-1 beta and IL-6 concentrations. Instead, we found evidence of an opposite effect on thyroid specific-gene Tg and NIS, that were decreased after 6-mer HA addition. Thyrocytes exposition to specific blocking antibodies for TLR-2, TLR-4 and CD44 abolished up-regulation of NF-kappa B activation and the consequent pro-inflammatory cytokine production, while restored Tg and NIS levels. A further goal of this study was demonstrate that also other LMW HA have pro inflammatory proprieties. These data suggest that HA fragments, through the involvement of TLR-2, TLR-4 and CD44 signaling cascade, contribute to prime the inflammatory response in thyrocytes and, by reducing the expression of thyroid-specific genes, could promote the loss of function of gland such as in Hashimoto's thyroiditis.