Interleukin 8 secretion from monocytes of subjects heterozygous for the deltaF508 cystic fibrosis transmembrane conductance regulator gene mutation is altered.
Patients with cystic fibrosis (CF) exhibit an excessive host inflammatory response. The aim of this study was to determine (i) whether interleukin 8 (IL-8) secretion is increased from monocytes from subjects heterozygous as well as homozygous for cystic fibrosis transmembrane conductance regulator (CFTR) mutations and (ii) whether this is due to increased cell surface lipopolysaccharide (LPS) receptors or, alternatively, increased activation of mitogen-activated protein kinases (MAPK). The basal level of IL-8 secretion was higher from monocytes from CF patients than from monocytes from healthy controls (P = 0.02) and obligate heterozygotes (parents of the CF patients). The 50% effective concentrations for LPS-induced IL-8 production for monocytes from both CF patients and obligate heterozygotes were 100-fold lower than those for monocytes from healthy controls (P < 0.05). No differences in the levels of IL-1beta production were seen between these groups. Expression of the LPS surface receptors CD14 and Toll-like receptor 4 were not different between CF patients and healthy controls. In contrast, phosphorylation of the MAPKs p38 and ERK occurred at lower doses of LPS in monocytes from patients heterozygous and homozygous for CFTR mutations. These results indicate that a single allelic CFTR mutation is sufficient to augment IL-8 secretion in response to LPS. This is not a result of increased LPS receptor expression but, rather, is associated with alterations in MAPK signaling.
Zaman
Munir M
MM
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Gelrud
Andres
A
Junaidi
Omer
O
Regan
Meredith M
MM
Warny
Michel
M
Shea
Julie C
JC
Kelly
Ciaran
C
O'Sullivan
Brian P
BP
Freedman
Steven D
SD
D000328:Adult; D016022:Case-Control Studies; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D020935:MAP Kinase Signaling System; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D009154:Mutation; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000032:analysis; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
C505032:CFTR protein, human; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator