Neutrophils in cystic fibrosis display a distinct gene expression pattern.
We compared gene expression in blood neutrophils (polymorphonuclear leukocytes, or PMNs) collected from healthy subjects with those of cystic fibrosis (CF) patients devoid of bacterial colonization. Macroarray analysis of 1050 genes revealed upregulation of 62 genes and downregulation expression of 27 genes in CF blood PMNs. Among upregulated genes were those coding for vitronectin, some chemokines (particularly CCL17 and CCL18), some interleukin (IL) receptors (IL-3, IL-8, IL-10, IL-12), all three colony-stimulating factors (G-, M-, GM-CSF), numerous genes coding for molecules involved in signal transduction, and a few genes under the control of gamma-interferon. In contrast, none of the genes coding for adhesion molecules were modulated. The upregulation of six genes in CF PMNs (coding for thrombospondin-1, G-CSF, CXCL10, CCL17, IKKvarepsilon, IL-10Ra) was further confirmed by qPCR. In addition, the increased presence of G-CSF, CCL17, and CXCL10 was confirmed by ELISA in supernatants of neutrophils from CF patients. When comparison was performed between blood and airway PMNs of CF patients, there was a limited difference in terms of gene expression. Only the mRNA expression of amphiregulin and tumor necrosis factor (TNF) receptor p55 were significantly higher in airway PMNs. The presence of amphiregulin was confirmed by ELISA in the sputum of CF patients, suggesting for the first time a role of amphiregulin in cystic fibrosis. Altogether, this study clearly demonstrates that blood PMNs from CF patients display a profound modification of gene expression profile associated with the disease, suggesting a state of activation of these cells.
Adib-Conquy
Minou
M
Unit Cytokines & Inflammation, Institut Pasteur, Paris, France.
Pedron
Thierry
T
Petit-Bertron
Anne-France
AF
Tabary
Olivier
O
Corvol
Harriet
H
Jacquot
Jacky
J
Clément
Annick
A
Cavaillon
Jean-Marc
JM
D000293:Adolescent; D066258:Amphiregulin; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D054414:Chemokine CCL17 / Q000097:blood; D054360:Chemokine CXCL1 / Q000097:blood; D054426:Chemokine CXCL2 / Q000097:blood; D018925:Chemokines / Q000097:blood / Q000235:genetics; D002648:Child; D003550:Cystic Fibrosis / Q000097:blood* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000097:blood / Q000235:genetics; D066255:EGF Family of Proteins; D005260:Female; D015870:Gene Expression; D006023:Glycoproteins / Q000097:blood / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000235:genetics; D007377:Interleukin-3 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D007378:Interleukins / Q000097:blood / Q000235:genetics; D008297:Male; D046228:Microarray Analysis; D018375:Neutrophil Activation / Q000235:genetics*; D009504:Neutrophils / Q000378:metabolism*; D012333:RNA, Messenger / Q000097:blood; D018123:Receptors, Interleukin / Q000097:blood / Q000235:genetics; D012016:Reference Values; D013183:Sputum / Q000737:chemistry / Q000166:cytology
C587848:AREG protein, human; D066258:Amphiregulin; D015415:Biomarkers; C106230:CCL17 protein, human; D054414:Chemokine CCL17; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D007377:Interleukin-3; D016209:Interleukin-8; D007378:Interleukins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D019005:Cystic Fibrosis Transmembrane Conductance Regulator