Hyaluronan-oligosaccharide-induced transcription of metalloproteases

Abstract

Activated dendritic epidermal Langerhans cells and metastatic tumour cells share many properties. Both cell types can invade the surrounding tissue, enter the lymphatic system and travel to regional lymph nodes. We have recently shown that fragments of the extracellular matrix component hyaluronan, which are typically produced at sites of inflammation, can activate dendritic cells. Upon activation, dendritic cells upregulate expression of matrix metalloproteases (MMPs). These observations prompted us to investigate whether exposure to hyaluronan fragments also induces MMP expression in tumour cells. Here, we report that MMP-9, MMP-13 and urokinase plasminogen activator are upregulated in murine 3LL tumour cells after exposure to mixed-size hyaluronan. Similarly upregulated MMP-9 and MMP-13 expression was observed in primary fibroblasts. By using sizefractionated hyaluronan preparations, we show that the enhanced expression of MMP-9 and MMP-13 is only induced by small hyaluronan (HA) fragments. Although our data suggest that HA-fragment-induced MMP-9 and MMP-13 expression is receptor mediated, they rule out an involvement of the hyaluronan receptors CD44, RHAMM/IHAP and TLR-4. Finally, we show that HA fragment-induced MMP-9 transcription is mediated via NF-κB. Our results suggest that the metastasis-associated HA degradation in tumours might promote invasion by inducing MMP expression.

Hyaluronan Fragments Act as an Endogenous Danger Signal by Engaging TLR2

“…1d demonstrates that LMW HA equally induces MIP-1␣ in TLR4 knockout and WT macrophages. Interestingly, Feiber with Termeer have also published data consistent with our findings that demonstrate that in murine embryonic fibroblasts oligosaccharide HA signals in a non-TLR4-dependent pathway (31). It is possible that different sizes of HA might signal differentially between TLR2 and TLR4.…”

“…On the basis of the ability of LMW HA to initiate inflammatory responses, we and others have hypothesized that LMW HA fragments were inducing activation via a TLR (15,(31)(32)(33). In this report, we identify TLR-2 as the HA fragment-activating receptor and demonstrate the ability of HMW HA to inhibit TLR-2 signaling.…”

Role of sialidase in Mycoplasma alligatoris-induced pulmonary fibroblast apoptosis

“…Although there is no consensus on the molecular mechanisms by which CD44 is linked to apoptosis (Hauptschein et al, 2005), HA fragments generated from the ECM by hyaluronidases stimulate HER2 and c-Src tyrosine kinase phosphorylation of cytoskeletal proteins, and Rho GTPase signaling, through desialylated CD44 receptor-specific networks (Ponta et al, 2003;Turley et al, 2002). As we observed in the present study, expression of CD44 itself may not change following ligand binding, depending on the cell type or basal level of CD44 expression (Ohno-Nakahara et al, 2004), but the observed increase in CD95 expression is consistent with transcription factor upregulation following HA fragment binding by desialylated CD44 (Fieber et al, 2004;Ohno et al, 2005). CD44 genes are annotated in fish, amphibian, and avian genomes, but our data establish for the first time that reptile cells also express a CD44 homolog, and further suggest that CD44-specific tyrosine kinase signaling networks are also conserved across vertebrate species.…”

The Hyaluronan Receptor for Endocytosis (HARE) Activates NF-κB-mediated Gene Expression in Response to 40–400-kDa, but Not Smaller or Larger, Hyaluronans

“…Binding of sHA, but not lHA, to CD44 significantly increases production of the inflammatory cytokine IL-6 (23). In 3LL and embryonic fibroblasts, oHA strongly stimulates NF-B activation by an unknown HA receptor and induces expression of metalloproteases MMP-9 and MMP-13 (24).…”