Figure 9

Schematic representation of the effect of 25-HC on cytokine release and toll-like receptor 3 response. 25-HC potentiated the release of IL-8 and IL-6 from HBEpC. 25-HC enhanced the NF-κB DNA binding activity and translocation of phosphorylated c-Jun into the nucleus. A NF-κB inhibitor, CAPE, an IκBα inhibitor, BAY 11–7085, an IKK-2 inhibitor and SC-514, except a JNK inhibitory peptide, L-JNKi1 inhibited the release of IL-8. Neither a P38 MAPK inhibitor, SB203580 nor a MEK1/2 inhibitor, U0126, affected the 25-HC-augmented IL-8 release. Agonists of liver X receptors, GW3965 and TO901317, did not enhance IL-8 release, and TO901317 conversely inhibited IL-8 release. Concerning the effect of 25-HC on the TLR3 response, 25-HC potentiated the release of IL-8 stimulated by TLR3 ligand, poly(I:C), and the potentiation was inhibited by CAPE, BAY 11–7085 and SC-514. 25-HC also potentiated the translocation of IRF3 into the nucleus and augmented the release of INF-β stimulated by poly(I:C). However, treatment with 25-HC did not affect the expression of TLR3. These data suggest that 25-HC stimulates the release of IL-8 and IL-6 mainly via NF-κB and enhances the release of IL-8 and INF-β after stimulation of TLR3 in human airway epithelial cells. LXR = Liver X receptor. BAY = BAY 11–8065.