In a new study entitled “An unexpected effect of TNF-α on F508del-CFTR maturation and function,” researchers found that a key factor released during inflammatory responses – TNF-alpha – can prevent premature degradation of mutated CFTR protein, the underlying mechanism of cystic fibrosis. The study was published in the open access platform F1000 Research.
Cystic fibrosis (CF) is a life-threatening disease caused by mutations in the Cftr gene (cystic fibrosis transmembrane conductance regulator gene). The CFTR protein is responsible for chloride and sodium ions being transported in and out of cells of multiple organs, including lungs. A defective or missing CFTR protein leads to the accumulation of sputum in patients’ respiratory tract, rendering CF patients more susceptible to infections. The recurrence of infections leads to a progressive decline in lung function, which is the main cause for CF deaths.
In this new study, authors investigated the most common mutation in the Cftr gene, the F508del mutation, and how it correlates with patients’ inflammatory status, when compared to the normal, wild type CFTR protein. They discovered that exposing Hela cells (a common cell line used in research) that express the F508del-CFTR protein when exposed to for a very short period, 10 minutes, of a key inflammatory cytokine (called TNF-α) induces the maturation of the mutated protein, therefore “fixing” these cells. The same phenotype was observed when authors repeated the experiment using human bronchial cells (HBE) expressing F508del-CFTR, and that the corrective effect upon F508del-CFTR protein lasted for at least 24hours. The team performed further studies to understand the mechanism underlying this beneficial alteration, and found that TNF-α prevents F508del-CFTR degradation before it is located at the cells membrane.
The clinical implications of these findings are highlighted by Aleksander Edelman, the study’s lead author who noted, “We hope to investigate whether TNF-α is linked to the severity of cystic fibrosis; if so then TNF-alpha levels might be one of a panel of molecules that could be used as a prognostic marker in the disease.”
Rebecca Lawrence, Managing Director of F1000Research, added, “These findings are an exciting development in the bid to find a cure for cystic fibrosis — a devastating disease that affects many thousands of people worldwide. It is really important that results of this nature are published in the public domain as quickly as possible for peer review and we are pleased to be able to facilitate this through our open science publishing platform.”