Abstract
Tumor necrosis factor (TNF)-α is a pleiotropic cytokine with intense pro-inflammatory and immunomodulatory properties, and anti-TNF-α biologics are effective therapies for various inflammatory diseases such as inflammatory bowel disease (IBD) and sepsis. Snake venom, as a traditional Chinese medicine, has been used in the treatment of inflammatory diseases in China for centuries. In this research, we constructed a venom gland T7 phage display library of the sea snake Hydrophis cyanocinctus to screen bioactive compounds that antagonize TNF-α and identified a novel nine-amino-acid peptide, termed hydrostatin-TL1 (H-TL1). In enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) analyses, H-TL1 inhibited the interaction between TNF-α and TNF receptor 1 (TNFR1). Further, H-TL1 attenuated the cytotoxicity of TNF-α in L929 cells as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. H-TL1 also decreased the mRNA expression of TNF-α/TNFR1 downstream targets and suppressed the phosphorylation of well-characterized proteins of downstream signal transduction pathways in HEK-293 cells. In vivo data demonstrated that H-TL1 protects animals against dextran sodium sulfate (DSS)-induced acute colitis and lipopolysaccharide (LPS)-induced acute shock. Given its significant anti-inflammatory activity in vitro and in vivo, H-TL1 is a potential peptide for the development of new agents to treat TNF-α-associated inflammatory diseases.
Keywords:
H-TL1; Hydrophis cyanocinctus; TNF-α; anti-inflammatory; inflammatory bowel diseases.
MeSH terms
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Acute Disease
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Animals
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / isolation & purification
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Anti-Inflammatory Agents / pharmacology*
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Cell Line
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Cell Survival / drug effects
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Colitis / chemically induced
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Colitis / drug therapy*
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Colitis / genetics
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Colitis / pathology
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Colubridae / metabolism
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Dextran Sulfate
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Elapid Venoms / chemical synthesis
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Elapid Venoms / isolation & purification
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Elapid Venoms / pharmacology*
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Extracellular Signal-Regulated MAP Kinases / chemistry
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Extracellular Signal-Regulated MAP Kinases / genetics
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Gene Expression Regulation
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HEK293 Cells
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Humans
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Lipopolysaccharides
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Mice
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Oligopeptides / chemical synthesis
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Oligopeptides / isolation & purification
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Oligopeptides / pharmacology*
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Peptide Library
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Phosphorylation
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Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors*
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Receptors, Tumor Necrosis Factor, Type I / chemistry
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Receptors, Tumor Necrosis Factor, Type I / genetics
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Reptilian Proteins / chemical synthesis
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Reptilian Proteins / isolation & purification
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Reptilian Proteins / pharmacology*
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Shock, Septic / chemically induced
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Shock, Septic / drug therapy*
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Shock, Septic / genetics
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Shock, Septic / pathology
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Signal Transduction
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Snake Venoms / chemistry*
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Snake Venoms / isolation & purification
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Transcription, Genetic
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / chemistry
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Tumor Necrosis Factor-alpha / genetics
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p38 Mitogen-Activated Protein Kinases / chemistry
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p38 Mitogen-Activated Protein Kinases / genetics
Substances
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Anti-Inflammatory Agents
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Elapid Venoms
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Lipopolysaccharides
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Oligopeptides
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Peptide Library
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Receptors, Tumor Necrosis Factor, Type I
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Reptilian Proteins
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Snake Venoms
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Tnfrsf1a protein, mouse
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Tumor Necrosis Factor-alpha
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hydrostatin-TL1 peptide, Hydrophis cyanocinctus
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Dextran Sulfate
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases