Effect of PPARγ agonist on Toll-like Receptor-4 signal transduction in melanoma

Introduction: There is increasing evidence that chronic activation of nuclear factor-kB (NF-kB),which is an essential signaling pathway involved in conveying inflammatory signals, is causallyrelated to cancer pathology. Activation of Toll-like receptor-4 (TLR-4) signalling bylipopolysaccharide (LPS), induces nuclear factor-kB (NF-kB). Interestingly, it is known thatactivation of peroxisome proliferator-activated receptors can exert anti-inflammatory effects andsuppresses NF-kB transcriptional activity. Herein, we investigated the modulatory effects ofpioglitazone as PPAR gamma agonist on LPS-mediated inflammatory responses and TLR4signaling in melanoma cancer cell line (B16F10).Materials Methods: B16F10 cells were treated with LPS (5 µg/ml) with or without pioglitazone(1,10,100,300 µM) and MTT assay was done .The expression of TLR4, myeloid differentiationprimary-response gene 88 (MyD88) and nuclear factor kappa-light-chain-enhancer of activated Bcells (NF-kB) mRNA were detected by quantitative real time-polymerase chain reactionmethod(qRT-PCR).Results: Results showed that pioglitazone treatment without LPS significantly decreased cellviability only at 300 µM (P<0.001).Pioglitazone treatment with LPS significantly decreased cellviability at all pioglitazone concentrations (P<0.001). By qRT-PCR analysis, results showed thatpioglitazone concentration-dependently downregulated mRNA expressions of TLR4, MyD88, NFkB.Conclusion: These results demonstrate that Pioglitazone negatively regulates TLR4 signaling inLPS-stimulated melanoma cells. It is may be exerts its anti-inflammatory effect by this way. Itprovides new insight to understand the mode of action of PPAR-γ agonist for its anti-cancer effects.