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-κB 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.

Renal Collecting Duct Epithelial Cells React to Pyelonephritis-Associated Escherichia coli by Activating Distinct TLR4-Dependent and -Independent Inflammatory Pathways

“…However, UPECs that stimulate the expression of RANTES in whole kidneys did not activate its expression in cultured MCDs. LPS has been shown to stimulate the production of both MCP-1 and RANTES in cultured mouse primary renal proximal tubule cells (21). Although the NF-B activation seems to be essential for LPS-mediated up-regulation of these two chemokines, the inhibition of JNK and p38 MAPK impairs the expression of RANTES but not of MCP-1 (21), suggesting that RANTES and MCP-1 are differently regulated.…”

“…Recent studies using the hemopoietic chimeric Lps n and Lps d mice demonstrated that bladder epithelial cells (19), as well as intrinsic renal epithelial cells (20), contribute together with bone marrow-derived cells to the initiation of antibacterial immunity. Murine and human renal tubule cells express some of the TLR expressed in hemopoietic cells and secrete chemokines upon LPS stimulation (21,22). In addition, TLR2 and TLR4 have been shown to be up-regulated in the distal nephron of inflamed, postischemic, reperfused kidneys (23).…”

Basigin/CD147 Promotes Renal Fibrosis after Unilateral Ureteral Obstruction

“…These staining patterns were the same as those previously reported. 40 Subconfluent tubular epithelial cells were incubated in serum-free medium for 24 hours to arrest and synchronize cell growth. After that, the medium was changed to fresh serum-free DMEM containing 5 ng/ml recombinant TGF-␤ (R&D Systems) for 0, 1, 3, 6, 12, and 24 hours in the time-course study.…”

Toll-Like Receptor 2 Agonists Exacerbate Accelerated Nephrotoxic Nephritis

“…TLR2 can be found on professional immune cells, including neutrophils, macrophages, and dendritic cells, but also on stromal cells throughout the body (14). Within the kidney, mRNA for TLR2 has been isolated from mouse renal tubular epithelial cells, and in situ hybridization has shown the presence of TLR2 in tubular epithelial cells and also within the glomerulus (15,16).…”