Activation of toll-like receptor 2 promotes the expression of inflammatory mediators and cell proliferation of human polycystic kidney disease cells.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive enlargement of fluid-filled cysts, leading to a decline in renal function. Toll-like receptors (TLR)-2 and TLR4 are pattern recognition receptors and components of the innate immune response. We found that mRNA levels for TLR2 and TLR4, an adaptor protein MyD88, and the transcription factor NF-κB were elevated in the kidneys of ADPKD patients and PKD mice. There was decreased expression of IκBα, an inhibitory protein sequestering NF-κB in the cytosol, and increased NF-κB nuclear translocation in human ADPKD kidneys compared with normal human kidneys (NHK). Pam3CSK4, a synthetic TLR2 agonist, increased the phosphorylation of IκBα, decreased its total levels, and caused NF-κB nuclear translocation and upregulation of pro-inflammatory mediators in cultured human ADPKD cells. Pam3CSK4 also increased phosphorylated ERK, a mitogen-activated protein kinase, and phosphorylated S6, a downstream target of the mTOR pathway, and accelerated ADPKD cell proliferation. By contrast, Pam3CSK4 did not affect NF-κB or ERK in NHK cells, but rather induced cytotoxicity, suggesting that TLR2 activation's effect was specific to ADPKD cells. Treatment with a TLR4 agonist did not affect NF-κB or ERK signaling in either ADPKD or NHK cells. Inhibition of TGF-β-activated kinase-1 (TAK1) effectively suppressed Pam3CSK4-induced NF-κB and ERK activation and the proliferation of ADPKD cells. These findings suggest that activation of TLR2 increases NF-κB-mediated-inflammatory mediators and ERK-dependent cell proliferation through TAK1 in ADPKD cells. We propose that the TLR2/TAK1 axis is a potential therapeutic target to reduce inflammation and cyst growth in ADPKD.