Center for Lung Research, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2650
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)- The NF- The precise NF- It is currently not clear how mutations in CFTR lead to abnormalities
of the NF- 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-
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REFERENCES
B.
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).
B pathway alterations present in CF epithelial cells
are not completely defined; however, we have found that I
B-
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 I
B-
, which can be found in the nucleus
(4). This is important because the hypophosphorylated form
of I
B-
, in contrast to I
B-
, neither anchors NF-
B in the
cytoplasm nor blocks DNA binding or transactivation by NF-
B
(2). Hypophosphorylated I
B-
appears to prevent
inactivation of NF-
B by newly produced I
B-
, resulting in
prolonged, exaggerated NF-
B activation.
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 I
B-
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.
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.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-61419, the Cystic Fibrosis Foundation, and the Department of Veterans Affairs.
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FOOTNOTES |
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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).
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REFERENCES |
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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
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
4.
Venkatakrishnan, A,
King G,
Stecenko AA,
Blackwell TR,
Brigham KL,
Christman JW,
and
Blackwell TS.
Exaggerated activation of NF-B and altered I
B-
processing in cystic fibrosis bronchial epithelial cells.
Am J Respir Cell Mol Biol
23:
396-403,
2000
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