title: IVIG inhibits TNF-α-induced MMP9 expression and activity in monocytes by suppressing NF-κB and P38 MAPK activation.
abstract: Matrix metalloproteinase-9 (MMP9) has been involved in inflammatory and pathologic processes of coronary artery lesions (CAL) in Kawasaki disease (KD). Intravenous immunoglobulin (IVIG), a traditional treatment for Kawasaki disease, could decrease the expressions of MMP9. The purpose of this study was to investigate the protective effect of IVIG in chemotactic migration of monocyte and the regulation of MMP9 induced by tumor necrosis factor-α (TNF-α) in U937s. Studies were carried out with real time polymerase chain reaction (RT-PCR), zymographic, Western blotting and immunofluorescence. U937s' migration was enhanced by TNF-α stimulation, while was inhibited by IVIG pretreatment. MMP9 expression and activity in U937s were also significantly enhanced by TNF-α and inhibited by IVIVG pretreatment. During inflammatory stimulus, nuclear factor kappa B (NF-κB) and P38 Mitogenactivated protein kinase (P38 MAPK) pathways play a significant role in regulating MMP9 gene expression. TNF-α induced nuclear translocation of NF-κB and P38 MAPK activation in U937s were inhibited significantly by IVIG. Furthermore, we clarified that nuclear NF-κB and P38 MAPK pathways play pivotal roles in regulating U937s' migration and MMP9 expressions using PDTC and SB203580, which were specific inhibitors of NF-κB and p38 MAPK pathways. IVIG displays striking biological effects, notably promoting monocyte migration. These effects involve the NF-κB and p38 pathways, and increased MMP9 activity. It might be a crucial mechanism of IVIG reducing the occurrence of CAL that IVIG inhibited monocytes expressing MMP9 and decreased chemotactic migration of monocyte.
authors.affiliation: Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiaotong University Shanghai 200062, China.
authors.forename: Cuizhen
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiaotong University Shanghai 200062, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiaotong University Shanghai 200062, China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiaotong University Shanghai 200062, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiaotong University Shanghai 200062, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Xiao
authors.affiliation: Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiaotong University Shanghai 200062, China.
authors.forename: Renjian
authors.initials: R
authors.lastname: Wang
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D016756:Immunoglobulins, Intravenous; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: IVIG; MMP9; NF-κB; P38 MAPK; monocyte migration