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.
引用
收藏
页码:6359 / 6366
页数:8
相关论文
共 50 条
[41]   Modulation of CD14 and TLR4•MD-2 Activities by a Synthetic Lipid A Mimetic [J].
Cighetti, Roberto ;
Ciaramelli, Carlotta ;
Sestito, Stefania Enza ;
Zanoni, Ivan ;
Kubik, Lukasz ;
Arda-Freire, Ana ;
Calabrese, Valentina ;
Granucci, Francesca ;
Jerala, Roman ;
Martin-Santamaria, Sonsoles ;
Jimenez-Barbero, Jesus ;
Peri, Francesco .
CHEMBIOCHEM, 2014, 15 (02) :250-258
[42]   Emodin Attenuates Lipopolysaccharide-Induced Acute Liver Injury via Inhibiting the TLR4 Signaling Pathway in vitro and in vivo [J].
Ding, Yan ;
Liu, Pan ;
Chen, Zhi-Lin ;
Zhang, Shao-Jun ;
Wang, You-Qin ;
Cai, Xin ;
Luo, Lei ;
Zhou, Xuan ;
Zhao, Lei .
FRONTIERS IN PHARMACOLOGY, 2018, 9
[43]   Dioscin alleviates lipopolysaccharide-induced acute lung injury through suppression of TLR4 signaling pathways [J].
Wang, Chuntao ;
Li, Qingnian ;
Li, Tianyu .
EXPERIMENTAL LUNG RESEARCH, 2020, 46 (1-2) :11-22
[44]   Free Thiol Group of MD-2 as the Target for Inhibition of the Lipopolysaccharide-induced Cell Activation [J].
Mancek-Keber, Mateja ;
Gradisar, Helena ;
Inigo Pestana, Melania ;
Martinez de Tejada, Guillermo ;
Jerala, Roman .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (29) :19493-19500
[45]   CD36 regulates lipopolysaccharide-induced signaling pathways and mediates the internalization of Escherichia coli in cooperation with TLR4 in goat mammary gland epithelial cells [J].
Cao, Duoyao ;
Luo, Jun ;
Chen, Dekun ;
Xu, Huifen ;
Shi, Huaiping ;
Jing, Xiaoqi ;
Zang, Wenjuan .
SCIENTIFIC REPORTS, 2016, 6
[46]   Plasminogen Activator Inhibitor-1 Regulates LPS-Induced TLR4/MD-2 Pathway Activation and Inflammation in Alveolar Macrophages [J].
Ren, Weiying ;
Wang, Zhonghui ;
Hua, Feng ;
Zhu, Lei .
INFLAMMATION, 2015, 38 (01) :384-393
[47]   Human TLR4 polymorphism D299G/T399I alters TLR4/MD-2 conformation and response to a weak ligand monophosphoryl lipid A [J].
Yamakawa, Natsuko ;
Ohto, Umeharu ;
Akashi-Takamura, Sachiko ;
Takahashi, Koichiro ;
Saitoh, Shin-Ichiroh ;
Tanimura, Natsuko ;
Suganami, Takayoshi ;
Ogawa, Yoshihiro ;
Shibata, Takuma ;
Shimizu, Toshiyuki ;
Miyake, Kensuke .
INTERNATIONAL IMMUNOLOGY, 2013, 25 (01) :45-52
[48]   Curcumin Analog L48H37 Prevents Lipopolysaccharide-Induced TLR4 Signaling Pathway Activation and Sepsis via Targeting MD2 [J].
Wang, Yi ;
Shan, Xiaoou ;
Dai, Yuanrong ;
Jiang, Lili ;
Chen, Gaozhi ;
Zhang, Yali ;
Wang, Zhe ;
Dong, Lili ;
Wu, Jianzhang ;
Guo, Guilong ;
Liang, Guang .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2015, 353 (03) :539-550
[49]   Decursin negatively regulates LPS-induced upregulation of the TLR4 and JNK signaling stimulated by the expression of PRP4 in vitro [J].
Ahmed, Muhammad Bilal ;
Ul Islam, Salman ;
Lee, Young Sup .
ANIMAL CELLS AND SYSTEMS, 2020, 24 (01) :44-52
[50]   Shikonin protects against D-Galactosamine and lipopolysaccharide-induced acute hepatic injury by inhibiting TLR4 signaling pathway [J].
Lin, Meng-Xiang ;
Yi, Yong-Xiang ;
Fang, Pei-Pei ;
Huang, Shan-Shan ;
Pan, Chen-Wei ;
Jin, Ling-Xiang ;
Zhang, Tong ;
Zhou, Guang-Yao .
ONCOTARGET, 2017, 8 (53) :91542-91550