Toll-like receptors (TLRs) are key components of innate immunity;they serve as the first line of defense against invading pathogens such as bacteria and viruses. The signaling initiated by TLRs is a double- edged sword. On the one hand, it may lead to confining or eliminating the invading organisms;on the other hand, a prolonged and exaggerated response can cause tissue and organ damage. Moreover, TLR signaling triggered by exogenous or endogenous ligands contributes to the pathogenesis of many chronic inflammatory diseases. For example, TLR2 and TLR4 are involved in atherosclerosis, autoimmune colitis, SLE, diabetes and Alzheimer's disease. Therefore, blockade of excessive TLR signaling is a therapeutic approach being pursued for these diseases. However, currently there are no approved TLR antagonists for clinic use. A Chinese herb, Sparganium stoloniferum has long been used in Traditional Chinese Medicine (TCM) for the treatment of several inflammatory diseases. Although much work has been done with extracts from this herb, no in-depth molecular investigation of its components has been performed. Recently, in an effort to isolate and functionally characterize single compounds from Sparganium stoloniferum tubers, we identified a novel compound, Sparstolonin B (SsnB) that selectively blocks TLR2- and TLR4-mediated signaling. This R21 proposal is aimed at continuing this exciting developmental research. The central hypothesis is that SsnB can be developed as an anti-inflammatory agent by virtue of its selective inhibitory effects on TLR2 and TLR4 signaling. To test this hypothesis, we propose two specific aims. SA1. To evaluate the toxicity and the anti- inflammatory efficacy of SsnB in vivo. We will first evaluate the in vivo toxicity of SsnB and then test if SsnB can suppress the inflammatory responses in endotoxemia and sepsis mouse models. SA2. To further elucidate the molecular mechanism by which SsnB blocks TLR2 and TLR4 signaling. We will identify the acting sites of SsnB on TLR2 and TLR4 signaling pathways. These studies will provide mechanistic insights into the therapeutic effects of Sparganium stoloniferum tubers in inflammatory diseases, translating a centuries-old alternative therapy modality into modern pharmacology. The identification and confirmation of SsnB as a TLR2 and TLR4 antagonist will provide an opportunity to develop a new anti-inflammatory agent. In future studies, we will test the therapeutic value of SsnB for several immune-related chronic inflammatory diseases such as atherosclerosis and diabetes.

Public Health Relevance

There is an unmet need for the treatment of chronic inflammatory diseases. We have identified a Chinese herb-derived small molecule compound, SsnB, with selective TLR2 and TLR4 blocking activities. Elucidation of the molecular mechanism and confirmation of the in vivo anti-inflammatory activity will lead to the development of SsnB into a selective TLR2 and TLR4 antagonist and an anti-inflammatory agent.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21AT006767-02
Application #
8453362
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Williamson, John S
Project Start
2012-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$166,113
Indirect Cost
$44,863
Name
University of South Carolina at Columbia
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
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Liang, Qiaoli; Dong, Shuihua; Lei, Lingling et al. (2015) Protective effects of Sparstolonin B, a selective TLR2 and TLR4 antagonist, on mouse endotoxin shock. Cytokine 75:302-9
Liu, Qing; Li, Jianping; Liang, Qiaoli et al. (2015) Sparstolonin B suppresses rat vascular smooth muscle cell proliferation, migration, inflammatory response and lipid accumulation. Vascul Pharmacol 67-69:59-66
Wang, Junfeng; Yu, Fang; Jia, Xuemei et al. (2015) MicroRNA-155 deficiency enhances the recruitment and functions of myeloid-derived suppressor cells in tumor microenvironment and promotes solid tumor growth. Int J Cancer 136:E602-13
Liu, Qing; Wang, Junfeng; Liang, Qiaoli et al. (2014) Sparstolonin B attenuates hypoxia-reoxygenation-induced cardiomyocyte inflammation. Exp Biol Med (Maywood) 239:376-84
Liu, Qing; Li, Jianping; Jubair, Shaiban et al. (2014) Sparstolonin B attenuates hypoxia-induced apoptosis, necrosis and inflammation in cultured rat left ventricular tissue slices. Cardiovasc Drugs Ther 28:433-9
Jia, Xuemei; Iwanowycz, Stephen; Wang, Junfeng et al. (2014) Emodin attenuates systemic and liver inflammation in hyperlipidemic mice administrated with lipopolysaccharides. Exp Biol Med (Maywood) 239:1025-1035
Kumar, Ambrish; Fan, Daping; Dipette, Donald J et al. (2014) Sparstolonin B, a novel plant derived compound, arrests cell cycle and induces apoptosis in N-myc amplified and N-myc nonamplified neuroblastoma cells. PLoS One 9:e96343
Jia, Xuemei; Yu, Fang; Wang, Junfeng et al. (2014) Emodin suppresses pulmonary metastasis of breast cancer accompanied with decreased macrophage recruitment and M2 polarization in the lungs. Breast Cancer Res Treat 148:291-302
Liang, Qiaoli; Yu, Fang; Cui, Xiaodong et al. (2013) Sparstolonin B suppresses lipopolysaccharide-induced inflammation in human umbilical vein endothelial cells. Arch Pharm Res 36:890-6

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