Findings from a recent study published in the Journal of Inflammation showed that knockdown of the CFTR gene of two intestinal epithelial cell lines triggers an inflammatory response, which may have clinical implications for patients with cystic fibrosis (CF).

Cystic fibrosis is the most prevalent life-shortening genetic disease among caucasians, affecting approximately one in 3,500 newborns, and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR dysfunction, along with other contributing factors, leads to a wide array of clinical symptoms, predominantly affecting the lungs and gastrointestinal system.

The origin of inflammation in CF-affected organs has been a topic of extensive and inconclusive research, and it remains unclear whether it is of primary or secondary origin. In airway cells, defective CFTR has been found to lead to impaired immune cell functions and amplified pro-inflammatory responses, whereas other studies have suggested that inflammation occurs secondary to bacterial infection. Similar to the airways, CFTR is highly expressed in the epithelial cells of the small and large intestine, with the greatest levels found in the duodenum.

To assess the hypothesis that genetic depletion of CFTR has an impact in the inflammatory status of human intestinal epithelial cell lines, in the study entitled “CFTR Knockdown induces pro-inflammatory changes in intestinal epithelial cells,” Geneviève Mailhot from the Department of Nutrition, Université de Montreal in Canada and colleagues performed a series of genetic analysis with the results revealing that CFTR gene knockdown caused a significant increase in basal secretion of endothelial cells (IL-8 as well as in IL-1β-induced secretion of IL-6 and −8).

Specifically, the researchers found that CFTR knockdown of two intestinal epithelial cell lines, called Caco-2/15 and HT-29, induced changes in the inflammatory response system as evidenced by an increase in gene expression and secretion of IL-6 and −8, as well as a greater activation of the ERK1/2 MAPK, IκBα and NF-κB pathways.

MAPKs are protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and pro-inflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis.

IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) is one member of a family of cellular proteins that function to inhibit the NF-κB transcription factor.

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens.

Based on the findings the researchers concluded that there is a support to “the theory that CFTR disruption, even moderate, may prevent cells from optimally responding to exogenous or endogenous challenges that trigger an inflammatory response. Such observations are of particular interest for CF patients who were found to display alterations in their intestinal microbiota, thus predisposing them to pathogens that may elicit exaggerated inflammatory responses. The emergence of CF intestinal organoid culture system will likely serve as a valuable tool for the further pathogenic characterization of CF-related intestinal inflammation.”