EDITORIAL FOCUS
Dysregulated NF-B activation in cystic fibrosis: evidence for a primary inflammatory disorder

Center for Lung Research, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2650

	ARTICLE

TOP ARTICLE REFERENCES

AIRWAY INFLAMMATION CHARACTERIZED by an influx of neutrophils and high concentrations of proinflammatory cytokines is a prominent and early feature of cystic fibrosis (CF). Until recently, it was thought that airway inflammation in CF was secondary to chronic bacterial infection resulting from impaired mucociliary clearance. However, new evidence supports the idea that dysregulation of the inflammatory response is an intrinsic component of the CF phenotype, and, therefore, airway inflammation may occur before or in the absence of bacterial infection. Several recent reports (1, 3, 4), including one by Weber et al. (5) in this issue of the American Journal of Physiology-Lung Cellular and Molecular Physiology, have demonstrated that lung epithelial cells expressing mutant CF transmembrane conductance regulator (CFTR) have increased production of proinflammatory cytokines and exaggerated activation of the transcriptional regulatory complex nuclear factor (NF)-B.

The NF-B family of transcription regulatory proteins has been implicated in the control of a variety of inflammatory processes in humans and in animal models of disease. NF-B influences production of a variety of proinflammatory cytokines that appear to be involved in the pathogenesis of CF lung disease. Identification of abnormalities of the NF-B pathway in cells with CFTR mutations provides a mechanistic explanation for the altered inflammatory mediator production by CF cells. Basal and tumor necrosis factor--stimulated NF-B activation have been shown to be upregulated in transformed human epithelial cells with CFTR mutations (1, 4). Dysregulation of NF-B activation, unrelated to extracellular Cl content or tonicity, has also been recently reported in primary CF bronchial gland epithelial cells (3).

The precise NF-B pathway alterations present in CF epithelial cells are not completely defined; however, we have found that IB- levels are increased in CF cells compared with normal and "corrected" CF epithelial cells. In addition, stimulation of CF epithelial cells results in increased production of new, hypophosphorylated IB-, which can be found in the nucleus (4). This is important because the hypophosphorylated form of IB-, in contrast to IB-, neither anchors NF-B in the cytoplasm nor blocks DNA binding or transactivation by NF-B (2). Hypophosphorylated IB- appears to prevent inactivation of NF-B by newly produced IB-, resulting in prolonged, exaggerated NF-B activation.

It is currently not clear how mutations in CFTR lead to abnormalities of the NF-B pathway. The manuscript by Weber et al. (5) sheds light on this important issue. Their findings demonstrate that lack of functional CFTR and not just accumulation of misfolded CFTR in the endoplasmic reticulum or some other by-product of the CTFR mutation leads to abnormal function of the NF-B pathway. They evaluated cells with CFTR mutations that produce proteins that are trafficked normally to the cell membrane but lack Cl channel function and cells with CFTR mutations that prevent translation of CFTR mRNA. Both of these types of CFTR mutations as well as the F508 mutation were associated with upregulation of NF-B activation and increased production of interleukin-8. Therefore, cell lines with defective CFTR Cl channel activity, regardless of the type of CFTR defect, have a proinflammatory phenotype. Elucidating the mechanisms by which abnormal Cl channel function determines dysregulated production of IB- and modulates NF-B activation is an important area for further investigation in CF. Interestingly, CFTR mutations like F508 that result in endoplasmic reticulum overload may cause NF-B upregulation by an additional mechanism independent of Cl channel function. As reported in the current study (5), expression of F508 CFTR in Chinese hamster ovary cells, which do not normally express CFTR, resulted in increased NF-B transcriptional activity, but expression of another type of CFTR mutation did not.

Together, these studies suggest a new paradigm that links mutations in CFTR to alterations in intracellular signal transduction, resulting in an exaggerated inflammatory response that is mediated, at least in part, by the NF-B pathway. The clinical implication of these findings is that treatment of CF patients with anti-inflammatory compounds that block the production of NF-B-dependent inflammatory mediators could interdict in the pathobiology induced by defective CFTR, potentially attenuating the progression of CF-related lung disease.

	ACKNOWLEDGEMENTS

This work was supported by National Heart, Lung, and Blood Institute Grant HL-61419, the Cystic Fibrosis Foundation, and the Department of Veterans Affairs.

	FOOTNOTES

Address for reprint requests and other correspondence: T. S. Blackwell, Center for Lung Research, Vanderbilt Univ. School of Medicine, T-1217, Nashville, TN 37232-2650 (E-mail: timothy.blackwell{at}mcmail.vanderbilt.edu).

	REFERENCES

TOP ARTICLE REFERENCES

1.   DiMango, E, Ratner AJ, Bryan R, Tabibi S, and Prince A. Activation of NF-B by adherent Pseudomonas aeruginosa in normal and cystic fibrosis respiratory epithelial cells. J Clin Invest 101: 2598-2605, 1988[Web of Science][Medline].

2.   Suyang, H, Phillips R, Douglas I, and Ghosh S. Role of unphosphorylated, newly synthesized IB in persistent activation of NF-B. Mol Cell Biol 16: 5444-5449, 1996[Abstract].

3.   Tabary, O, Escotte S, Couetil JP, Hubert D, Dusser D, Puchelle E, and Jacquot J. High susceptibility for cystic fibrosis human airway gland cells to produce IL-8 through the I kappa B kinase alpha pathway in response to extracellular NaCl content. J Immunol 164: 3377-3384, 2000[Abstract/Free Full Text].

4.   Venkatakrishnan, A, King G, Stecenko AA, Blackwell TR, Brigham KL, Christman JW, and Blackwell TS. Exaggerated activation of NF-B and altered IB- processing in cystic fibrosis bronchial epithelial cells. Am J Respir Cell Mol Biol 23: 396-403, 2000[Abstract/Free Full Text].

5.   Weber, AJ, Soong G, Bryan R, Saba S, and Prince A. Activation of NF-B in airway epithelial cells is dependent on CFTR trafficking and Cl channel function. Am J Physiol Lung Cell Mol Physiol 281: L71-L78, 2001[Abstract/Free Full Text].