title: Characterization of sparstolonin B, a Chinese herb-derived compound, as a selective Toll-like receptor antagonist with potent anti-inflammatory properties.
abstract: Blockade of excessive Toll-like receptor (TLR) signaling is a therapeutic approach being actively pursued for many inflammatory diseases. Here we report a Chinese herb-derived compound, sparstolonin B (SsnB), which selectively blocks TLR2- and TLR4-mediated inflammatory signaling. SsnB was isolated from a Chinese herb, Spaganium stoloniferum; its structure was determined by NMR spectroscopy and x-ray crystallography. SsnB effectively inhibited inflammatory cytokine expression in mouse macrophages induced by lipopolysaccharide (LPS, a TLR4 ligand), Pam3CSK4 (a TLR1/TLR2 ligand), and Fsl-1 (a TLR2/TLR6 ligand) but not that by poly(I:C) (a TLR3 ligand) or ODN1668 (a TLR9 ligand). It suppressed LPS-induced cytokine secretion from macrophages and diminished phosphorylation of Erk1/2, p38a, IκBα, and JNK in these cells. In THP-1 cells expressing a chimeric receptor CD4-TLR4, which triggers constitutive NF-κB activation, SsnB effectively blunted the NF-κB activity. Co-immunoprecipitation showed that SsnB reduced the association of MyD88 with TLR4 and TLR2, but not that with TLR9, in HEK293T cells and THP-1 cells overexpressing MyD88 and TLRs. Furthermore, administration of SsnB suppressed splenocyte inflammatory cytokine expression in mice challenged with LPS. These results demonstrate that SsnB acts as a selective TLR2 and TLR4 antagonist by blocking the early intracellular events in the TLR2 and TLR4 signaling. Thus, SssB may serve as a promising lead for the development of selective TLR antagonistic agents for inflammatory diseases.
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina 29209, USA.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Liang
authors.forename: Qinan
authors.initials: Q
authors.lastname: Wu
authors.forename: Jihong
authors.initials: J
authors.lastname: Jiang
authors.forename: Jin'ao
authors.initials: J
authors.lastname: Duan
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Mark D
authors.initials: MD
authors.lastname: Smith
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Prakash
authors.initials: P
authors.lastname: Nagarkatti
authors.forename: Daping
authors.initials: D
authors.lastname: Fan
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D016207:Cytokines; D004365:Drugs, Chinese Herbal / Q000737:chemistry* / Q000494:pharmacology; D057809:HEK293 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D019684:Magnoliopsida / Q000737:chemistry*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D015394:Molecular Structure; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004365:Drugs, Chinese Herbal; D006576:Heterocyclic Compounds, 4 or More Rings; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C561322:sparstolonin B; D020929:Mitogen-Activated Protein Kinase Kinases