A new study revealed that the cystic fibrosis transmembrane conductance regulator (CFTR) plays an important role in regulating intestinal inflammatory responses. The study, entitled “CFTR Knockdown induces pro inflammatory changes in intestinal epithelial cells,” was published in the Journal of Inflammation by researchers from the Research Centre and Université de Montreal in Montreal, Quebec.
Cystic Fibrosis (CF) is a rare but well-described chronic, genetic disease characterized by mutations in the CFTR protein, and is associated with a build-up of mucous and chronic polymicrobial infections that impact the respiratory and digestive systems. Exacerbated inflammation is a relevant characteristic of cystic fibrosis airways but not an exclusive one, since it has been observed systemically and more recently in extrapulmonary CF-affected tissues such as the pancreas and intestine.
The association between the pathogenesis of CF-related inflammation and the role of CFTR in the inflammatory process is not well understood. As a result, the research team hypothesized that genetic depletion of CFTR plays a crucial role in the inflammatory status of human intestinal epithelial cell lines. To test this, the researchers induced inflammatory conditions by adding the human recombinant tumor necrosis factor (TNF) or Interleukin-1β (IL-1β) and genetically depleted CFTR expression from cell lines using short hairpin RNA interference (shRNAi). shRNAi is a post-transcriptional process triggered by the introduction of double-stranded RNA (dsRNA) which induces gene silencing in a sequence-specific manner.
They observed that the CFTR gene and protein deficiency induced a significant increase in basal secretion of IL-8 as well as in IL-1β-induced secretion of IL-6 and -8, while the levels of the anti-inflammatory cytokine, IL-10, were unaffected by CFTR deficiency. The results from animal models also confirmed the in vitro findings.
Altogether, the results call attention to the role played by CFTR in the regulation of intestinal inflammatory responses. Moreover, these data supported the hypothesis that CFTR seems to play functions that go further than its role as a chloride channel, and its disruption may prevent cells from optimally responding to exogenous or endogenous stimuli.
Overall, the researchers conclude, this study may be of particular relevance to cystic fibrosis patients who have changes in their intestinal microbiota, making them susceptible to pathogens that could induce exaggerated inflammatory responses.