Down-regulation of the anti-inflammatory protein annexin A1 in cystic fibrosis knock-out mice and patients.
Cystic fibrosis is a fatal human genetic disease caused by mutations in the CFTR gene encoding a cAMP-activated chloride channel. It is characterized by abnormal fluid transport across secretory epithelia and chronic inflammation in lung, pancreas, and intestine. Because cystic fibrosis (CF) pathophysiology cannot be explained solely by dysfunction of cystic fibrosis transmembrane conductance regulator (CFTR), we applied a proteomic approach (bidimensional electrophoresis and mass spectrometry) to search for differentially expressed proteins between mice lacking cftr (cftr(tm1Unc), cftr-/-) and controls using colonic crypts from young animals, i.e. prior to the development of intestinal inflammation. By analyzing total proteins separated in the range of pH 6-11, we detected 24 differentially expressed proteins (>2-fold). In this work, we focused on one of these proteins that was absent in two-dimensional gels from cftr-/- mice. This protein spot (molecular mass, 37 kDa; pI 7) was identified by mass spectrometry as annexin A1, an anti-inflammatory protein. Interestingly, annexin A1 was also undetectable in lungs and pancreas of cftr-/- mice, tissues known to express CFTR. Absence of this inhibitory mediator of the host inflammatory response was associated with colonic up-regulation of the proinflammatory cytosolic phospholipase A2. More importantly, annexin A1 was down-regulated in nasal epithelial cells from CF patients bearing homozygous nonsense mutations in the CFTR gene (Y122X, 489delC) and differentially expressed in F508del patients. These results suggest that annexin A1 may be a key protein involved in CF pathogenesis especially in relation to the not well defined field of inflammation in CF. We suggest that decreased expression of annexin A1 contributes to the worsening of the CF phenotype.
Bensalem
Noura
N
INSERM U467, Faculté de médecine Necker, Université Paris-Descartes, France.
Ventura
Ana Paula
AP
Vallée
Benoît
B
Lipecka
Joanna
J
Tondelier
Danielle
D
Davezac
Noélie
N
Dos Santos
Alexandre
A
Perretti
Mauro
M
Fajac
Anne
A
Sermet-Gaudelus
Isabelle
I
Renouil
Michel
M
Lesure
Jean-François
JF
Halgand
Frédéric
F
Laprévote
Olivier
O
Edelman
Aleksander
A
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D017305:Annexin A1 / Q000737:chemistry / Q000378:metabolism*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics; D003106:Colon / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency* / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics*; D015180:Electrophoresis, Gel, Two-Dimensional; D006720:Homozygote; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009297:Nasal Mucosa / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D017305:Annexin A1; D018389:Codon, Nonsense; D019005:Cystic Fibrosis Transmembrane Conductance Regulator