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Int J Biol Sci. 2013;9(1):94-107. doi: 10.7150/ijbs.5246. Epub 2013 Jan 3.

AGE-LDL activates Toll like receptor 4 pathway and promotes inflammatory cytokines production in renal tubular epithelial cells.

Author information

1
Division of Nephrology, Nanfang Hospital, Southern Medical University, Research Institute of Nephrology Guangdong Province, Key Lab for Organ Failure Research, Ministry of Education, Guangzhou, P.R. China.

Abstract

BACKGROUND/AIMS:

Accumulation of advanced glycation end-products, the well-recognized pro-inflammatory molecules, has been detected in renal tissues including tubules. The aim of the present study was to investigate the role of advanced glycation end-products modified low density lipoprotein (AGE-LDL) in inflammatory cytokines production in human proximal tubular epithelial cells and the underlying mechanism.

METHODS:

The Interleukin-6 (IL-6) and Interleukin-8 (IL-8) production was examined by real-time PCR and ELISA. The expression of Toll-like receptor 2 and 4 (TLR2/4) was detected by flow cytometry and western blot. The interaction of TLR2/4 with AGE-LDL was examined by co-immunoprecipitation assay. The involvement of MyD88 and the downstream molecules in inflammatory cytokines production was examined by siRNA and pharmacologic inhibitors, respectively.

RESULTS:

AGE-LDL interacted with TLR2 and TLR4. TLR4 siRNA showed stronger inhibition on AGE-LDL-induced IL-6 and IL-8 production than that of TLR2 siRNA. Silencing MyD88, but not TRIF, inhibited AGE-LDL-induced IL-6 and IL-8 production. AGE-LDL stimulation led to phosphorylation of JNK, p38, Akt and the p65 subunit of nuclear factor-κB (NF-κB). Pharmacologic inhibitor of Akt suppressed AGE-LDL-induced activation of NF-κB, but the inhibitor of JNK, p38 or ERK1/2 had no effect. Blocking MyD88, p38, JNK, Akt or NF-κB attenuated AGE-LDL-triggered IL-6 production.

CONCLUSION:

AGE-LDL induced IL-6 and IL-8 production via TLR2/4-MyD88-dependent pathway in tubular epithelial cells. These data suggest that activation of TLRs signaling in tubular epithelial cells by AGE-LDL might be a novel mechanism for the tubulointerstitial inflammation.

KEYWORDS:

AGE-LDL; IL-6.; MyD88; NF-κB; Toll like receptor

PMID:
23355795
PMCID:
PMC3555149
DOI:
10.7150/ijbs.5246
[Indexed for MEDLINE]
Free PMC Article

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