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Clinical and Diagnostic Laboratory Immunology, September 2004, p. 819-824, Vol. 11, No. 5
1071-412X/04/$08.00+0     DOI: 10.1128/CDLI.11.5.819-824.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Interleukin 8 Secretion from Monocytes of Subjects Heterozygous for the F508 Cystic Fibrosis Transmembrane Conductance Regulator Gene Mutation Is Altered

Munir M. Zaman,^1, Andres Gelrud,^1, Omer Junaidi,¹ Meredith M. Regan,² Michel Warny,¹ Julie C. Shea,¹ Ciaran Kelly,¹ Brian P. O'Sullivan,³ and Steven D. Freedman^1*

Division of Gastroenterology,¹ Division of Medicine, Beth Israel Deaconess Medical Center, Boston,² Department of Pediatrics, University of Massachusetts Memorial Health Care, University of Massachusetts Medical School, Worcester, Massachusetts³

Received 6 January 2004/ Returned for modification 9 March 2004/ Accepted 3 May 2004

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-1ß 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.

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* Corresponding author. Mailing address: Beth Israel Deaconess Medical Center, Dana 552, 330 Brookline Ave., Boston, MA 02215. Phone: (617) 667-5576. Fax: (617) 667-0536. E-mail: sfreedma{at}bidmc.harvard.edu.

M.M.Z. and A.G. contributed equally to this work.

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Clinical and Diagnostic Laboratory Immunology, September 2004, p. 819-824, Vol. 11, No. 5
1071-412X/04/$08.00+0     DOI: 10.1128/CDLI.11.5.819-824.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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