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T. Orita, K. Kimura, T. Nishida; Poly(I:C) Induced Adhesion Molecule Expression Through Cross-Signaling Between NF-B and Phosphoinositide 3-Kinase-Akt Pathway in Human Corneal Fibroblasts. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6212.
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We previously showed that polyinosinic-polycytidylic acid [poly(I:C)], an analog of viral double-stranded RNA, induced the expression of adhesion molecules and cytokines in cultured corneal fibroblasts in a manner dependent on nuclear factor (NF)-ΚB signaling. We have now investigated the roles of nuclear factor (NF)-ΚB and phosphoinositide 3-kinase (PI3K)-Akt signaling pathways and their cross-talking in the poly(I:C)-induced expression of adhesion molecules in corneal fibroblasts.
Human corneal fibroblasts were cultured with poly(I:C) in the absence or presence of IΚB kinase 2 (IKK2) inhibitor (an inhibitor of NF-ΚB activation) or the PI3K inhibitor LY294002. The expression of vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, ICAM-2, and E-selectin as well as the phosphorylation of the NF-ΚB-inhibitory protein IΚB-α and Akt were examined by immunoblot analysis. The subcellular localization of adhesion molecules and the p65 subunit of NF-ΚB was determined by immunofluorescence analysis.
Poly(I:C) increased the expression of VCAM-1 and ICAM-1 but not that of ICAM-2 or E-selectin in corneal fibroblasts. Poly(I:C) also induced the phosphorylation of IΚB-α and Akt as well as the nuclear translocation of p65. The poly(I:C)-induced expression of VCAM-1 and ICAM-1 was attenuated by both IKK2 inhibitor and LY294002, the latter of which also inhibited the poly(I:C)-induced phosphorylation of IΚB-α.
The NF-ΚB and PI3K-Akt signaling pathways mediate the poly(I:C)-induced up-regulation of VCAM-1 and ICAM-1 in corneal fibroblasts, with PI3K acting upstream of NF-ΚB activation. These pathways thus likely modulate local immune and inflammatory responses to viral infection in the corneal stroma.
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