title: Protective effects of Sparstolonin B, a selective TLR2 and TLR4 antagonist, on mouse endotoxin shock.
abstract: Sepsis is characterized by an overwhelming systemic inflammation and multiple organ injury. Toll-like receptors (TLRs) 2 and 4 mediate these inflammatory responses. Sparstolonin B (SsnB), isolated from Chinese herb Scirpus yagara, is a new selective TLR2/4 antagonist. Herein, we report that SsnB inhibited the expression of various inflammatory mediators such as tumor necrosis factor (TNF-α), interleukin (IL)-1β, IL-6, and chemokine (C-C motif) ligand 2 (CCL-2) in lipopolysaccharide (LPS)- or Pam3csk4-stimulated macrophages. Moreover, in LPS-stimulated macrophages, the downregulation of peroxisome proliferator-activated receptor γ (PPAR-γ) was reversed by SsnB dose-dependently; and SsnB had synergistic inhibitory effects with rosiglitazone, a PPAR-γ agonist, on TNF-α and IL-6 expression in LPS-stimulated macrophages. The effects of SsnB were further evaluated in a mouse endotoxin shock model. When intraperitoneal injected in mice 2 days before or 1-2h after LPS challenge, SsnB attenuated the body temperature reduction and decreased the mortality. SsnB pre-treatment significantly suppressed LPS-induced increase of TNF-α and IL-6 in serum, lungs and livers, and substantially attenuated lung dysfunction in mice. In vivo toxicity test showed that at doses as high as 500 mg/kg, SsnB did not cause death of mice. These results suggest that SsnB protects mice against endotoxin shock by inhibiting production of multiple cytokines and lung dysfunction. In conclusion, our findings indicate that SsnB may be used in the prevention and treatment of endotoxin shock.
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: liangqiaoli2008@163.com.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Liang
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Shuihua
authors.initials: S
authors.lastname: Dong
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Lei
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Jianfang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory for TCM Formulae Research, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Jin'ao
authors.initials: J
authors.lastname: Duan
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA.
authors.forename: Daping
authors.initials: D
authors.lastname: Fan
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D047495:PPAR gamma / Q000819:agonists / Q000096:biosynthesis; D000077154:Rosiglitazone; D018805:Sepsis / Q000473:pathology; D012772:Shock, Septic / Q000188:drug therapy* / Q000517:prevention & control; D045162:Thiazolidinediones / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004365:Drugs, Chinese Herbal; D006576:Heterocyclic Compounds, 4 or More Rings; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D055666:Lipopeptides; D008070:Lipopolysaccharides; D047495:PPAR gamma; C508075:Pam(3)CSK(4) peptide; D045162:Thiazolidinediones; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C561322:sparstolonin B; D000077154:Rosiglitazone
keywords: Cytokine; Inflammation; Sepsis; Sparstolonin B; Toll-like receptor