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Tenri, Japan

Tenri University is a Japanese private university in Tenri, Nara Prefecture, an independent part of the secular mission of Tenrikyo. It was established in February 1925 as the coeducational Tenri Foreign Language School , enrolling 104 students, and was reorganised as a university in April 1949. It has a strong reputation in Japan for foreign language study and judo. Wikipedia.

Increased fbronectin fragments are thought to contribute to joint destruction in osteoarthritis (OA). However, the mechanism whereby fbronectin fragments cause catabolic activities is not totally understood. While COOH-terminal heparin-binding fibronectin fragment (HBFN-f) has been shown to activate nuclear factor (NF)-κB pathway, intracellular upstream events that cause NF-κB up-regulation in response to HBFN-f remain unclear. Thus, this study was aimed to elucidate the involvement of phosphoinositide-3-OH kinase (PI3K)/Akt pathway in NF-κB activation by HBFN-f in OA chondrocytes. In chondrocyte monolayer cultures, HBFN-f stimulated nitric oxide (NO) production in association with phosphorylation of NF-κB and Akt. Inhibition studies using LY294002 revealed the requirement of PI3K/Akt pathway for NO production and NF-κB activation by HBFN-f. Anti-CD44 treatment with anti-CD44 antibody and hyaluronan resulted in significant inhibition of HBFN-f actions on NO, NF-κB, and Akt. Herein, we provided the frst evidence that HBFN-f activates PI3K/Akt pathway leading to up-regulation of NF-κB through interaction with CD44.

Hyaluronan (HA) of high molecular weight is used in the treatment of osteoarthritis and rheumatoid arthritis by intra-articular injection. While HA has been shown to suppress nuclear factor (NF)-κB activation by proinflammatory cytokines and lipopolysaccharide (LPS), intracellular upstream events that cause NF-κB down-regulation in response to HA remain unclear. Thus, this study was performed to investigate the involvement of phosphoinositide-3-OH kinase (PI3K)/Akt in the inhibition of the LPS-activated NF-κB pathway by HA in U937 macrophages. In adherent U937 macrophage cultures, pretreatment with HA of 2700 kDa (1 mg/ml, 1 h) significantly inhibited interleukin-6 (IL-6) production by LPS (200 ng/ml, 24 h)-stimulated U937 cells. LPS (200 ng/ml) activated Akt and NF-κB, whereas HA (1 mg/ml) down-regulated LPS-stimulated phosphorylation of Akt and NF-κB. Inhibition studies using LY294002 (20 μM) revealed the requirement of the PI3K/Akt pathway for LPS-stimulated IL-6 production and NF-κB activation. Pretreatment with anti-intercellular adhesion molecule-1 (ICAM-1) antibody (20 μg/ml) reversed the inhibitory effects of HA on LPS-induced production of IL-6 and activation of Akt and NF-κB. Herein, we provided the first evidence that HA suppresses the LPS-activated PI3K/Akt pathway, leading to down-regulation of NF-κB with diminished IL-6 production through interaction with ICAM-1. © The Japanese Pharmacological Society.

Yasuda T.,Tenri University
Tohoku Journal of Experimental Medicine | Year: 2010

Prostaglandin E2 (PGE2) is one of the key mediators of inflammation in affected joints of rheumatoid arthritis (RA). Intra-articular injection of high molecular weight hyaluronan (HA) into RA knee joints relieves arthritic pain. Although HA has been shown to inhibit PGE2 production in cytokine-stimulated synovial fibroblasts, it remains unclear how HA suppresses PGE2 production in activated cells. Furthermore, HA effect on macrophages has rarely been investigated in spite of their contribution to RA joint pathology. This study was aimed to investigate the inhibitory mechanism of HA on lipopolysaccharide (LPS)-stimulated PGE2 production in U937 human macrophages. Stimulation of U937 macrophages with LPS enhanced PGE2 production in association with increased protein levels of cyclooxygenase-2 (COX-2). Pretreatment with HA of 2,700 kDa resulted in suppression of the LPS-mediated induction of COX-2, leading to a decrease in PGE2 production. Likewise, the LPS-stimulated PGE2 production was inhibited by the pretreatment with a specific COX2 inhibitor, NS-398, or a specific inhibitor of nuclear factor (NF)-κB, BAY11-7085. HA also decreased the degree of phosphorylation and nuclear translocation of NF-κB enhanced by LPS. Fluorescence cytochemistry demonstrated that HA bound to CD44, the principal HA receptor, on U937 macrophages. Anti-CD44 antibody reversed the inhibitory effects of HA on the LPS-mediated increase in PGE2 production, COX-2 induction, and activation of NF-κB. These results indicate that HA suppresses the LPS-stimulated PGE2 production via CD44 through down-regulation of NF-κB. Administration of HA into RA joints may decrease PGE2 production by activated macrophages, which could result in improvement of arthritic pain. © 2010 Tohoku University Medical Press.

High molecular weight hyaluronan (HA) is widely used in the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA) by intra-articular injection. However, comparative studies of HA actions on catalytically activated cartilages in different pathologic conditions have rarely been investigated. This study was aimed to compare the inhibitory effects of HA on nitric oxide (NO) production by COOH-terminal heparin-binding fibronectin fragment (HBFN-f) between normal and diseased cartilages. When articular cartilage explants from normal, OA, or RA joints were incubated with HBFN-f, the RA and OA cartilages produced higher levels of NO compared with normal cartilage. Pretreatment with 2700 kDa HA resulted in significant suppression of HBFN-f-stimulated NO production in OA and RA cartilages. While CD44 was up-regulated in OA and RA cartilages, anti-CD44 antibody reversed HA inhibition of HBFN-f action in those cartilages. The present results clearly demonstrated that HA blocked HBFN-f actions in OA and RA cartilages through interaction with CD44. HA, which targets CD44 highly expressed on OA and RA chondrocytes, could suppress catabolic actions by fibronectin fragments like HBFN-f in diseased cartilage.

This study examined the activation of p38 mitogen-activated protein kinase with matrix metalloproteinase-13 (MMP-13) production by a synthetic peptide derived from type II collagen (CB12-II) and its inhibition by high molecular weight hyaluronan (HA) in chondrocytes. When cartilage explants or isolated chondrocytes in monolayer were incubated with CB12-II, the peptide (50 μM, 72 h) activated p38 in association with enhanced MMP-13 production. Inhibition studies with SB203580 (0.1 - 1 μM) indicated the requirement of p38 for CB12-II-induced MMP-13 production. Pretreatment with 2700 kDa HA (1 mg/ml, 1 h) resulted in significant suppression of CB12-II-stimulated MMP-13 production in cartilage as well as in chondrocyte monolayer cultures. HA (1 mg/ml) suppressed p38 activation by CB12-II, leading to a decrease in MMP-13 production. The antibody (20 μg/ml) to intercellular adhesion molecule-1 (ICAM-1), which has been recognized as a receptor of HA on chondrocytes, reversed the HA effect on CB12-II action. Thus, the present study clearly demonstrated that high molecular weight HA suppressed CB12-II-activated p38 via ICAM-1 in articular chondrocytes. HA could down-regulate the catabolic action of type II collagen fragments in osteoarthritic joints through the mechanism demonstrated in this study. © The Japanese Pharmacological Society.

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