Down-regulation of the anti-inflammatory protein annexin A1 in cystic fibrosis knock-out mice and patients

doi:10.1074/mcp.M500019-MCP200

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Submitted on January 17, 2005
Revised on June 7, 2005
Accepted on July 12, 2005

Down-regulation of the anti-inflammatory protein annexin A1 in cystic fibrosis knock-out mice and patients

Noura Bensalem, Ana Paula Ventura, Benoît Vallée, Joanna Lipecka, Danielle Tondelier, Noélie Davezac, Alexandre Dos Santos, Mauro Perretti, Anne Fajac, Isabelle Sermet-Gaudelus, Michel Renouil, Jean-François Lesure, Frederic Halgand, Olivier Laprevote, and Aleksander Edelman

Faculté de Medecine Necker, INSERM U467, Paris 75730

Corresponding Author: edelman{at}necker.fr

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. Since CF pathophysiology cannot be explained solely by dysfunction of CFTR, we applied a proteomic approach (bi-dimensional electrophoresis and mass spectrometry) to search for differentially expressed proteins between mice lacking cftr (cftrtm1Unc, cftr-/-) and controls using colonic crypts from young animals i.e. prior to the development of intestinal inflammation. By analysing total proteins separated in the range of pH 6-11, we have detected 24 differentially expressed proteins (> 2 fold). In this work, we focused on one of these proteins that was absent in 2D gels from cftr-/- mice. This protein spot (MW 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 pro-inflammatory 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.

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