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Identification of a Novel Human MD-2 Splice Variant That Negatively Regulates Lipopolysaccharide-Induced TLR4 Signaling
被引:30
作者:
Gray, Pearl
[1
]
Michelsen, Kathrin S.
[2
]
Sirois, Cherilyn M.
[3
]
Lowe, Emily
[1
]
Shimada, Kenichi
[1
]
Crother, Timothy R.
[1
]
Chen, Shuang
[1
]
Brikos, Constantinos
[2
]
Bulut, Yonca
[1
]
Latz, Eicke
[3
,4
]
Underhill, David
[2
]
Arditi, Moshe
[1
]
机构:
[1] Univ Calif Los Angeles, Cedars Sinai Med Ctr, David Geffen Sch Med, Div Pediat Infect Dis & Immunol, Los Angeles, CA 90048 USA
[2] Univ Calif Los Angeles, Ctr Inflammatory Bowel Dis, David Geffen Sch Med, Burns & Allen Res Inst, Los Angeles, CA 90048 USA
[3] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Worcester, MA 01605 USA
[4] Univ Bonn, Inst Innate Immun, D-5300 Bonn, Germany
基金:
美国国家卫生研究院;
关键词:
INTERLEUKIN-1 RECEPTOR ANTAGONIST;
NF-KAPPA-B;
CUTTING EDGE;
SECRETED MD-2;
SOLUBLE MD-2;
EXPRESSION;
LPS;
BINDING;
COMPLEX;
PROTEIN;
D O I:
10.4049/jimmunol.0903543
中图分类号:
R392 [医学免疫学];
Q939.91 [免疫学];
学科分类号:
100102 ;
摘要:
Myeloid differentiation factor 2 (MD-2) is a secreted gp that assembles with TLR4 to form a functional signaling receptor for bacterial LPS. In this study, we have identified a novel alternatively spliced isoform of human MD-2, termed MD-2 short (MD-2s), which lacks the region encoded by exon 2 of the MD-2 gene. Similar to MD-2, MD-2s is glycosylated and secreted. MD-2s also interacted with LPS and TLR4, but failed to mediate LPS-induced NF-kappa B activation and IL-8 production. We show that MD-2s is upregulated upon IFN-gamma, IL-6, and TLR4 stimulation and negatively regulates LPS-mediated TLR4 signaling. Furthermore, MD-2s competitively inhibited binding of MD-2 to TLR4. Our study pinpoints a mechanism that may be used to regulate TLR4 activation at the onset of signaling and identifies MD-2s as a potential therapeutic candidate to treat human diseases characterized by an overly exuberant or chronic immune response to LPS. The Journal of Immunology, 2010, 184: 6359-6366.
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页码:6359 / 6366
页数:8
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