TLR4-mediated IRAK1 activation induces TNF-alpha expression via JNK-dependent NF-kappa B activation in human bronchial epithelial cells

초록

The purpose of this study was to identify the mechanism of lipopolysaccharide (LPS)-induced expression of tumor necrosis factor (TNF)-alpha in BEAS-2B. Toll-like receptor (TLR)4-specific siRNA was found to completely abolish the LPS-induced expression of MyD88 and TNF-alpha. There was enhanced binding of MyD88 with IRAK1 following LPS treatment, and MyD88- or IRAK1-specific siRNAs decreased the expression of TNF-alpha. In addition, IRAK1 siRNA downregulated the phosphorylation of PKC alpha, demonstrating that PKC alpha is a downstream effector of IRAK1. Inhibition of PKC alpha completely blocked the activation of AKT, whereas inhibition of AKT with a PI3K inhibitor prevented the LPS-induced expression of TNF-alpha. We found that AKT activated JNK, which then stimulated phosphorylation of I kappa-B alpha, resulting in NF-kappa B activation. As expected, inhibition of NF-kappa B completely inhibited the expression of TNF-alpha. Taken together, our results suggest that LPS induces TNF-alpha expression by activating NF-kappa B via the PKC/PI3K/AKT/JNK pathway, which is in turn dependent on MyD88/IRAK1.

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