Figure 2.

Selected examples of the miRNA network regulating IL-8. 1. microRNAs regulating the AKT-dependent NF-kB: miR-155-5p expression is potentiated by NF-kB and is elevated in CF lung epithelial cells and circulating CF neutrophils biopsied from CF patients. High levels of miR-155 specifically reduce the levels of SHIP1, thereby promoting PI3K/Akt activation. Phospho-Akt levels are therefore elevated in CF lung epithelial cells and can be specifically lowered by either antagomir-155 or elevated expression of SHIP1. Elevated miR-155-5p contributes to the pro-inflammatory expression of IL-8 in CF lung epithelial cells by lowering SHIP1 expression and thereby activating the PI3K/Akt signaling pathway (104). 2. transcriptional regulation of IL-8 gene expression: IL-8 promoter is under the control of transcription factors enhancing IL-8 mRNA production (examples are NF-κB, AP-1, C/EBPβ, CHOP, and CREB); furthermore, IL-8 gene expression is repressed by Oct-1 and by NF-κB repressing factor (NRF). All these transcription factors are regulated by microRNAs. 3. post-transcriptional miRNA-dependent regulation of IL-8: Fabbri et al. identified miR-93 as a miRNA that is decreased in cystic fibrosis IB3-1 and Cufi-1 cells infected with P. aeruginosa. The possible involvement of miR-93 in IL-8 gene regulation was validated using luciferase vectors and the results obtained indicate that IL-8 protein expression is post-transcriptionally regulated by interactions of the IL-8 mRNA with the inhibitory miR-93 (105). The involvement of microRNAs in IL-8 is also supported by the study of Oglesby et al. (106) who identified miR-17 as a miRNA regulating IL-8. Interestingly, its expression was decreased in adult CF bronchial brushings and bronchial epithelial cells chronically stimulated with Pseudomonas-conditioned medium (106). 5′-UTR, 3′-UTR: 5′ and 3′ untranslated region of the IL-8 mRNA; CDS, coding sequences.