title: Suppression of matrix metalloproteinase-9 expression by andrographolide in human monocytic THP-1 cells via inhibition of NF-κB activation.
abstract: There is much evidence indicating that human leukemic cells and monocytes/macrophages synthesize, and secrete, several matrix metalloproteinases (MMPs), and participate in the degradation of extracellular matrix components in tissue lesions. In this study, we investigated the effects and mechanisms of andrographolide, extracted from the herb Andrographis paniculata, on human monocytic MMPs expression and activation. Andrographolide (1-50 μM) exhibited concentration-dependent inhibition of MMP-9 activation, induced by either tumor necrosis factor-α (TNF-α), or lipopolysaccharide (LPS), in THP-1cells. In addition, andrographolide did not present an inhibitory effect on MMP-9 enzymatic activity at a concentration of 50 μM. By contrast, enzyme-linked immunosorbent assay (ELISA) showed that andrographolide partially affect TIMP-1 levels. Western blot analysis showed that both TNF-α, and LPS stimulators attenuated MMP-9 protein expression in a concentration-dependent manner. Using reverse transcription polymerase chain reaction (RT-PCR), we found that andrographolide suppressed expression of MMP-9 messenger RNA. Furthermore, we also found that andrographolide could significantly inhibit the degradation of inhibitor-κB-α (IκB-α) induced by TNF-α. We used electrophoretic mobility shift assay and reporter gene detection to show that andrographolide also markedly inhibited NF-κB signaling, anti-translocation and anti-activation. In conclusion, we demonstrate that andrographolide attenuates MMP-9 expression, and its main mechanism might involve the NF-κB signal pathway. These results provide new opportunities for the development of new anti-inflammatory and leukemic therapies.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Department of Dermatology, Taipei Medical University Hospital and Department of Dermatology, Taipei Medical University-Shuang Ho Hospital, Taipei 11031, Taiwan.
authors.forename: Woan-Ruoh
authors.initials: WR
authors.lastname: Lee
authors.forename: Chi-Li
authors.initials: CL
authors.lastname: Chung
authors.forename: Che-Jen
authors.initials: CJ
authors.lastname: Hsiao
authors.forename: Yung-Chen
authors.initials: YC
authors.lastname: Chou
authors.forename: Po-Jen
authors.initials: PJ
authors.lastname: Hsueh
authors.forename: Po-Chih
authors.initials: PC
authors.lastname: Yang
authors.forename: Jing-Shiun
authors.initials: JS
authors.lastname: Jan
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Cheng
authors.forename: George
authors.initials: G
authors.lastname: Hsiao
mesh_terms: D035685:Andrographis / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D017930:Genes, Reporter; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology*; D021381:Protein Transport; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects
chemical_list: D004224:Diterpenes; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011480:Protease Inhibitors; D012333:RNA, Messenger; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C030419:andrographolide; D020780:Matrix Metalloproteinase 9