Azithromycin Reduces Exaggerated Cytokine Production by M1 Alveolar Macrophages in Cystic Fibrosis

被引:99
作者
Meyer, Magali [1 ]
Huaux, Francois [2 ]
Gavilanes, Ximena [1 ]
van den Brule, Sybille [2 ]
Lebecque, Patrick [3 ]
Lo Re, Sandra [2 ]
Lison, Dominique [2 ]
Scholte, Bob [4 ]
Wallemacq, Pierre [1 ]
Leal, Teresinha [1 ]
机构
[1] Univ Catholique Louvain, Dept Clin Chem, Brussels, Belgium
[2] Univ Catholique Louvain, Unit Ind Toxicol & Occupat Med, Brussels, Belgium
[3] Univ Catholique Louvain, Div Paediat Pulmonol, Brussels, Belgium
[4] Erasmus MC, Dept Cell Biol, Rotterdam, Netherlands
关键词
cystic fibrosis; cystic fibrosis transmembrane conductance regulator; inflammation; macrophages; azithromycin; TRANSMEMBRANE CONDUCTANCE REGULATOR; EARLY PULMONARY INFLAMMATION; AIRWAY EPITHELIAL-CELLS; LONG-TERM AZITHROMYCIN; NITRIC-OXIDE; CONTROLLED-TRIAL; IN-VITRO; LUNG; CHEMOKINE; EXPRESSION;
D O I
10.1165/rcmb.2008-0155OC
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Macrophages phagocyte pathogenic microorganisms and orchestrate immune responses by producing a variety of inflammatory mediators. The cystic fibrosis (CF) transmembrane conductance regulator chloride channel has been reported to be of pivotal importance for macrophage functions. The exact phenotype and role of macrophages in CF is still unknown. Alveolar and peritoneal macrophages were monitored in CIF mice homozygous for the F508 del mutation and in wild-type control animals. Classical (M1) and alternative (M2) macrophage polarization and responses to LIPS from Pseudomonas aeruginosa were investigated, and the effect of azithromycin was examined in both cell populations. We show that alveolar macrophage counts were 1.7-fold higher in CIF as compared with wild-type mice. The macrophage-related chemokine, chemokine C-C motif ligand (CCL)-2, was found to be at least 10-fold more abundant in the alveolar space of mutant mice. Cell count and CCL-2 protein levels were also increased in the peritoneal cavity of CIF mice. Both M1 and M2 macrophage polarization were significantly enhanced in alveolar and peritoneal cells from F508del-CF mice as compared with control animals. LPS-stimulated expression of proinflammatory mediators, such as nitric oxide synthase-2, IL-1 beta, and CCL-2, was increased, whereas anti-inflammatory IL-10 expression was decreased in CIF macrophages. Azithromycin, added to cell cultures at 1 mg/liter, significantly reduced proinflammatory cytokine expression (IL-1 beta, CCL-2, TNF-alpha) in M1-induced CF and wild-type alveolar macrophages. Our findings indicate that CF macrophages are ubiquitously accumulated, and that these cells are polarized toward classical and alternative activation status. Azithromycin down-regulates inflammatory cytokine production by M1-polarized CIF alveolar macrophages.
引用
收藏
页码:590 / 602
页数:13
相关论文
共 54 条
[1]   Novel effects of azithromycin on tight junction proteins in human airway epithelia [J].
Asgrimsson, V ;
Gudjonsson, T ;
Gudmundsson, GH ;
Baldursson, O .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2006, 50 (05) :1805-1812
[2]   Systemic inflammatory mediators and cystic fibrosis genotype [J].
Augarten, A ;
Paret, G ;
Avneri, I ;
Akons, H ;
Aviram, M ;
Bentur, L ;
Blau, H ;
Efrati, O ;
Szeinberg, A ;
Barak, A ;
Kerem, E ;
Yahav, J .
CLINICAL AND EXPERIMENTAL MEDICINE, 2004, 4 (02) :99-102
[3]   Altered respiratory epithelial cell cytokine production in cystic fibrosis [J].
Bonfield, TL ;
Konstan, MW ;
Berger, M .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 1999, 104 (01) :72-78
[4]   INFLAMMATORY CYTOKINES IN CYSTIC-FIBROSIS LUNGS [J].
BONFIELD, TL ;
PANUSKA, JR ;
KONSTAN, MW ;
HILLIARD, KA ;
HILLIARD, JB ;
GHNAIM, H ;
BERGER, M .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1995, 152 (06) :2111-2118
[5]   NORMAL BRONCHIAL EPITHELIAL-CELLS CONSTITUTIVELY PRODUCE THE ANTIINFLAMMATORY CYTOKINE INTERLEUKIN-10, WHICH IS DOWN-REGULATED IN CYSTIC-FIBROSIS [J].
BONFIELD, TL ;
KONSTAN, MW ;
BURFEIND, P ;
PANUSKA, JR ;
HILLIARD, JB ;
BERGER, M .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 1995, 13 (03) :257-261
[6]   Dysregulated interleukin-8 secretion and NF-κB activity in human cystic fibrosis nasal epithelial cells [J].
Carrabino, Salvatore ;
Carpani, Daniela ;
Livraghi, Alessandra ;
Di Cicco, Maurizio ;
Costantini, Diana ;
Copreni, Elena ;
Colombo, Carla ;
Conese, Massimo .
JOURNAL OF CYSTIC FIBROSIS, 2006, 5 (02) :113-119
[7]   Azithromycin selectively reduces tumor necrosis factor alpha levels in cystic fibrosis airway epithelial cells [J].
Cigana, Cristina ;
Assael, Baroukh Maurice ;
Melotti, Paola .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2007, 51 (03) :975-981
[8]   Anti-inflammatory effects of azithromycin in cystic fibrosis airway epithelial cells [J].
Cigana, Cristina ;
Nicolis, Elena ;
Pasetto, Matteo ;
Assael, Baroukh Maurice ;
Melotti, Paola .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2006, 350 (04) :977-982
[9]   Long term effects of azithromycin in patients with cystic fibrosis: a double blind, placebo controlled trial [J].
Clement, A. ;
Tamalet, A. ;
Leroux, E. ;
Ravilly, S. ;
Fauroux, B. ;
Jais, J-P .
THORAX, 2006, 61 (10) :895-902
[10]   CFTR regulates phagosome acidification in macrophages and alters bactericidal activity [J].
Di, Anke ;
Brown, Mary E. ;
Deriy, Ludmila V. ;
Li, Chunying ;
Szeto, Frances L. ;
Chen, Yimei ;
Huang, Ping ;
Tong, Jiankun ;
Naren, Anjaparavanda P. ;
Bindokas, Vytautas ;
Palfrey, H. Clive ;
Nelson, Deborah J. .
NATURE CELL BIOLOGY, 2006, 8 (09) :933-U52