| RRC ID |
43212
|
| 著者 |
Kon S, Ikesue M, Kimura C, Aoki M, Nakayama Y, Saito Y, Kurotaki D, Diao H, Matsui Y, Segawa T, Maeda M, Kojima T, Uede T.
|
| タイトル |
Syndecan-4 protects against osteopontin-mediated acute hepatic injury by masking functional domains of osteopontin.
|
| ジャーナル |
J Exp Med
|
| Abstract |
Osteopontin (OPN) is a T helper type 1 immunoregulatory cytokine that plays a critical role in various inflammatory disorders. OPN exerts proinflammatory reactions through interaction with integrin receptors. OPN function can be modulated by protease digestion. However, the molecular mechanisms that regulate OPN function in vivo have not been elucidated. There are two putative heparin-binding domains (HBDs) within the OPN molecule, which may bind both heparin and heparin-like glycosaminoglycans such as syndecan. We show that expression of OPN and syndecan-4 is significantly up-regulated after concanavalin-A (ConA) injection. Syndecan-4 binds to one of the HBDs of OPN, which overlaps with the thrombin cleavage site of OPN. When OPN is associated with syndecan-4, syndecan-4 masks both the thrombin cleavage and the integrin binding sites within OPN. Importantly, syndecan-4-deficient (Syn4KO) mice are more susceptible to hepatic injury, and the thrombin-cleaved form of OPN is significantly elevated in Syn4KO mice as compared with wild-type mice after ConA injection. Finally, we demonstrate that administration of purified syndecan-4 protects mice from ConA-induced hepatic injury. Thus, syndecan-4 is a critical intrinsic regulator of inflammatory reactions via its effects on OPN function and is a potential novel therapeutic tool for treating inflammatory diseases.
|
| 巻・号 |
205(1)
|
| ページ |
25-33
|
| 公開日 |
2008-1-21
|
| DOI |
10.1084/jem.20071324
|
| PII |
jem.20071324
|
| PMID |
18158320
|
| PMC |
PMC2234375
|
| MeSH |
Animals
Concanavalin A / pharmacology
Disease Models, Animal
Gene Expression Regulation
Heparan Sulfate Proteoglycans / chemistry
Heparin / chemistry
Humans
Inflammation
Liver / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Osteopontin / chemistry*
Osteopontin / metabolism*
Protein Structure, Tertiary
Syndecan-4 / metabolism
Syndecan-4 / physiology*
|
| IF |
11.743
|
| 引用数 |
42
|
|
WOS 分野
|
MEDICINE, RESEARCH & EXPERIMENTAL
IMMUNOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
CHO-K1(RCB0285) |
