Oral Administration of High Molecular Weight Hyaluronan (900 kDa) Controls Immune System via Toll-like Receptor 4 in the Intestinal Epithelium

Abstract

Low molecular weight hyaluronan enhances or induces inflammation through toll-like receptor 4 (TLR-4).However, the effects of high molecular weight hyaluronan (HA900) on TLR-4 are unknown. In this study, HA900 (900 kDa) was administered orally to MRL-lpr/lpr mice, a Th-1-type autoimmune disease model. Lymphoaccumulation of double-negative T cells, which is enhanced by proinflammatory cytokines, was suppressed by HA900 treatment. Cytokine array analysis showed that HA900 treatment enhanced production of interleukin-10, an anti-inflammatory cytokine, and down-regulated chemokine production. HA900 colocalized with TLR-4 on the luminal surface of epithelial cells in the large intestine. These cells are parts of the immune system and express cytokines. DNA array analysis of the tissue from the large intestine showed that HA900 treatment up-regulated suppressor of cytokine signaling 3 (SOCS3) expression and down-regulated pleiotrophin expression. Treatment of cultured double-negative T cells from MRL-lpr/lpr mice with pleiotrophin rescued these cells. SOCS3, which is known to suppress inflammation, was enhanced by HA900 treatment. In TLR-4 knockdown HT29 cells (a cell line derived from large intestinal cells), HA900 did not bind to HT29 cells and did not up-regulate SOCS3 expression. Our results suggest that oral administration of HA900 modulates Th-1-type autoimmune disease and inflammation by up-regulating SOCS3 expression and down-regulating pleiotrophin expression via TLR-4 in intestinal epithelial cells.Many reports have shown that low molecular weight hyaluronan (HA) 2 enhances or induces inflammation via toll-like receptor 4 (TLR-4) (1, 2). It is well known that the functions of HA are molecular weight-dependent (3, 4). Therefore, we hypothesized that the actions of HA via TLR-4 depend on its molecular weight. MRL-lpr/lpr mice (3) are characterized by lymphoaccumulation of double-negative T cells (DNT cells), i.e. lymph node enlargement in their lymph nodes and spleens, and proliferation of these cells is enhanced by proinflammatory cytokines (5, 6).TLR-4 is a type of HA receptor found on the surface of large intestinal epithelial cells, which form part of the immune system and express cytokines. SOCS3 expression suppresses inflammation and arthritis (7-9).In this study, we showed that oral administration of high molecular weight HA (HA900) up-regulated suppressor of cytokine signaling 3 (SOCS3). In large intestinal epithelial cells, HA900 bound to TLR-4 on the cell surface and was not systemically absorbed.Furthermore, HA900 suppressed pleiotrophin expression, which is implicated in inflammation, in intestinal tissue and in arthritis. Pleiotrophin mRNA in the spinal cord is significantly up-regulated after induction of experimental autoimmune encephalomyelitis (10, 11), and pleiotrophin is expressed in adults with inflammatory diseases, particularly in rheumatoid arthritis (12). These findings suggest that HA900 controls the immune system through up-regulation of SOCS3 and downregulation of pleiotrophin. This ...

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