title: Hyaluronan fragments induce the synthesis of MCP-1 and IL-8 in cultured human peritoneal mesothelial cells.
abstract: Human peritoneal mesothelial cells (HMC) play an important role in inflammatory processes by their ability to produce various cytokines and chemokines, such as monocyte chemoattractant protein 1 (MCP-1) and interleukin 8 (IL-8). In this study we investigated the effect of experimentally generated hyaluronan (HA) fragments, degradation products of the extracellular matrix component hyaluronan, which accumulate at inflammatory sites, on the expression of MCP-1 and IL-8 in cultured HMC. MCP-1 and IL-8 mRNA expression was determined by RNase protection assays, and protein levels in the supernatants were measured by enzyme-linked immunosorbent assays. HA fragments with a molecular mass of approximately 1-7x10(5) daltons upregulate MCP-1 and IL-8 synthesis in HMC dose and time dependently. The effect of HA fragments could be blocked by Ro31-8220, a specific protein kinase C inhibitor, and by PD98059, an inhibitor of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Upregulation of chemokine synthesis was preceded by an increase in NF-kappaB and AP-1 DNA-binding activity, suggesting that these transcription factors are activated to increase MCP-1 and IL-8 expression by HA fragments. These data demonstrate that HA fragments markedly enhance the mRNA expression and protein synthesis of MCP-1 and IL-8 in HMC. In concert with previous findings, our observations indicate that enhanced levels of HA, which are present in the peritoneal cavity of peritoneal dialysis patients, may account for a locally increased chemokine production.
authors.affiliation: Medizinische Klinik Innenstadt, Klinikum der Ludwig-Maximilians Universität, Munich, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Haslinger
authors.forename: S
authors.initials: S
authors.lastname: Mandl-Weber
authors.forename: A
authors.initials: A
authors.lastname: Sellmayer
authors.forename: T
authors.initials: T
authors.lastname: Sitter
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008970:Molecular Weight; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D010530:Peritoneal Dialysis; D010537:Peritoneum / Q000166:cytology / Q000276:immunology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018960:Hyaluronan Receptors; D007211:Indoles; D016209:Interleukin-8; D016328:NF-kappa B; D010446:Peptide Fragments; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D006820:Hyaluronic Acid; D011493:Protein Kinase C; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C064758:Ro 31-8220