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B Kinase 
Pathway in Response to Extracellular NaCl Content1
*
Institut National de la Santé et de la Recherche Médicale, Unité 514, Institut Fédératif de Recherche 53, Centre Hospitalier Universitaire, Maison Blanche, Reims, France;
Service de Pneumologie, Hôpital Cochin, Paris, France; and
Département de Chirurgie Cardio-Vasculaire, Hôpital Broussais, Paris, France
Increasing evidence suggests that in airways from cystic fibrosis
(CF) patients, inflammation may precede bacterial infection and be
related to an endogenous dysregulation of proinflammatory cytokines in
airway epithelial cells. Several investigators have reported that, in
CF airway fluids, elevated NaCl concentrations may also contribute to
the diseased state by inhibiting the bactericidal properties of airway
fluid. Because many proinflammatory cytokines are transcriptionally
regulated by the NF-
B, we investigated whether an elevated
extracellular NaCl content in airway fluids significantly impaired the
regulation of the NF-B/IB
complex and the chemokine IL-8
production in primary non-CF and CF human bronchial gland epithelial
cells. Exposure of non-CF gland cells to hypotonic (85 mM) NaCl
solution, compared with isotonic (115 mM) NaCl and hypertonic (170 mM)
NaCl solutions, resulted in a significant decrease in IL-8 production
that was paralleled by a strong inhibition of activated NF-B
associated with an increased cytosolic expression of IB and a
decrease in the IB kinase protein level. In CF gland cells, we
demonstrated that, compared with the high IL-8 in an hypertonic
solution, the release of IL-8 was significantly reduced 2-fold in an
isotonic solution and 5-fold in a hypotonic solution. Strikingly,
exposure of CF bronchial gland cells to either hypotonic or isotonic
milieu did not result in a marked inhibition of the activated
NF-B/IB system. This is the first demonstration that primary
human CF bronchial gland cells exhibit abnormally high IL-8 production
through constitutively activated NF-B and high IB kinase
level, whatever the hypo-, iso-, and hypertonic NaCl
milieu.
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