Aminoglycosides are widely used for the treatment of cystic fibrosis (CF), a fatal, autosomal, recessive genetic disease characterized by persistent pulmonary infection and extensive lung inflammation. In addition to their role as antibiotics, aminoglycosides have been shown to act as suppressors of nonsense mutations that generate premature translation termination (PTCs). PTCs constitute the molecular basis of many genetic diseases, including CF (5-10% of cystic fibrosis alleles contain PTCs) as lead to the synthesis of truncated non-functional or partially functional protein. Suppression of translation terminations at PTCs (read-through) has been developed as a therapeutic strategy to restore full-lenght protein in several genetic diseases. Phenotypic consequences of PTCs can be exacerbated by the nonsense-mediated mRNA decay (NMD) pathway that detect and degrade PTC containing mRNA. Modulation of NMD, therefore, is also of interest as a potential target for the suppression therapy. Tobramycin is an aminoglycoside antibiotic, normally used to treat Pseudomonas aeruginosa pulmonary infection in CF patients. In the present study we have investigated, on one hand, the properties of Tobramycin as a modulator of the expression of IL-8 associated with inflammation of the CF airway pathology in CF IB3-1 cells induced with pro-inflammatory cytokine TNF- α. On the other hand, by using the yeast as a genetic system, we have examined the ability of Tobramycin to suppress PTCs as a function of the presence or absence of NMD. Results demonstrate that Tobramycin is a good inhibitor of IL-8 expression and exhibits read-through ability on PTCs in conditions in which NMD is not operating in the cell.

Tobramycin inhibits interleukin-8 gene expression and acts as suppressor of premature termination codons in the absence of NMD

GAMBARI, Roberto;BORGATTI, Monica
2012

Abstract

Aminoglycosides are widely used for the treatment of cystic fibrosis (CF), a fatal, autosomal, recessive genetic disease characterized by persistent pulmonary infection and extensive lung inflammation. In addition to their role as antibiotics, aminoglycosides have been shown to act as suppressors of nonsense mutations that generate premature translation termination (PTCs). PTCs constitute the molecular basis of many genetic diseases, including CF (5-10% of cystic fibrosis alleles contain PTCs) as lead to the synthesis of truncated non-functional or partially functional protein. Suppression of translation terminations at PTCs (read-through) has been developed as a therapeutic strategy to restore full-lenght protein in several genetic diseases. Phenotypic consequences of PTCs can be exacerbated by the nonsense-mediated mRNA decay (NMD) pathway that detect and degrade PTC containing mRNA. Modulation of NMD, therefore, is also of interest as a potential target for the suppression therapy. Tobramycin is an aminoglycoside antibiotic, normally used to treat Pseudomonas aeruginosa pulmonary infection in CF patients. In the present study we have investigated, on one hand, the properties of Tobramycin as a modulator of the expression of IL-8 associated with inflammation of the CF airway pathology in CF IB3-1 cells induced with pro-inflammatory cytokine TNF- α. On the other hand, by using the yeast as a genetic system, we have examined the ability of Tobramycin to suppress PTCs as a function of the presence or absence of NMD. Results demonstrate that Tobramycin is a good inhibitor of IL-8 expression and exhibits read-through ability on PTCs in conditions in which NMD is not operating in the cell.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1934212
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? 0
social impact