Differential regulation of inflammation by inflammatory mediators in cystic fibrosis lung epithelial cells.

Motohiro Tsuchiya, Parameet Kumar, Sharmistha Bhattacharyya, Sangbrita Chattoraj, Meera Srivastava, Harvey B Pollard, Roopa Biswas

Molecular and Cell Biology Program, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2013 Mar

filter terms:

Cystic fibrosis (CF) is due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which cause a massively proinflammatory phenotype in the CF airway. The chemical basis of the inflammation is hyperproduction of interleukin-8 (IL-8) by CF airway epithelial cells, based on both an intrinsic mutation-dependent mechanism and by infection. In infection-free, cultured CF lung epithelial cells, high levels of the microRNA (miR), miR-155, is responsible for hyperexpression of IL-8. However, whether infection-induced IL-8 expression in CF cells is also mediated by miR-155 is not known. We have hypothesized that miR-155 might be a general mediator of enhanced IL-8 expression in CF cells, either in response to other cytokine/chemokine mediators of inflammation, or after exposure to infectious agents. Here we find that a reduction in miR-155 accompanies suppression of IL-8 by either the anti-inflammatory cytokine IL-10 or by inhibition of ambient IL-1β with a neutralizing antibody. However, attempts to elevate IL-8 levels with either intact bacteria [viz. a mucoid strain of Pseudomonas aeruginosa (PA)], or lipopolysaccharide were unable to elevate miR-155 above its intrinsically high level in the absence of these agents. Instead, in response to PA infection, the CF cells modestly suppress the expression of miR-155, and express a novel set of miRs, including miR-215. We find that ex vivo CF lung epithelial cells also express high levels of both miR-155 and miR-215. The predicted module of infection-induced mRNA targets focuses on activation of the NFκB-signaling pathway, and on the proapoptotic p53-signaling pathway. We interpret these data to suggest that that CF lung epithelial cells respond to PA or bacterial cell products with a novel miR program that may carry with it serious challenges to survival.

Citation

Motohiro Tsuchiya, Parameet Kumar, Sharmistha Bhattacharyya, Sangbrita Chattoraj, Meera Srivastava, Harvey B Pollard, Roopa Biswas. Differential regulation of inflammation by inflammatory mediators in cystic fibrosis lung epithelial cells. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. 2013 Mar;33(3):121-9