title: Roles of toll-like receptors in C-C chemokine production by renal tubular epithelial cells.
abstract: Pyelonephritis, in which renal tubular epithelial cells are directly exposed to bacterial component, is a major predisposing cause of renal insufficiency. Although previous studies have suggested C-C chemokines are involved in the pathogenesis, the exact source and mechanisms of the chemokine secretion remain ambiguous. In this study, we evaluated the involvement of Toll-like receptors (TLRs) in C-C chemokine production by mouse primary renal tubular epithelial cells (MTECs). MTECs constitutively expressed mRNA for TLR1, 2, 3, 4, and 6, but not for TLR5 or 9. MTECs also expressed MD-2, CD14, myeloid differentiation factor 88, and Toll receptor-IL-1R domain-containing adapter protein/myeloid differentiation factor 88-adapter-like. Synthetic lipid A and lipoprotein induced monocyte chemoattractant protein 1 (MCP-1) and RANTES production in MTECs, which strictly depend on TLR4 and TLR2, respectively. In contrast, MTECs were refractory to CpG-oligodeoxynucleotide in chemokine production, consistently with the absence of TLR9. LPS-mediated MCP-1 and RANTES production in MTECs was abolished by NF-kappaB inhibition, but unaffected by extracellular signal-regulated kinase inhibition. In LPS-stimulated MTECs, inhibition of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase significantly decreased RANTES, but did not affect MCP-1 mRNA induction. Thus, MTECs have a distinct expression pattern of TLR and secrete C-C chemokines in response to direct stimulation with a set of bacterial components.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Research Institute for Disease Mechanism and Control, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Naotake
authors.initials: N
authors.lastname: Tsuboi
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yoshikai
authors.forename: Seiichi
authors.initials: S
authors.lastname: Matsuo
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Iwami
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nagai
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matsuguchi
mesh_terms: D000818:Animals; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology; D029721:Drosophila Proteins; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D048031:JNK Mitogen-Activated Protein Kinases; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008050:Lipid A / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C408982:CPG-oligonucleotide; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D019742:Chemokines, CC; D016207:Cytokines; D029721:Drosophila Proteins; D008050:Lipid A; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases