Expression and modulation of ICAM-1, TNF-alpha and RANTES in human alveolar macrophages from lung-transplant recipients in vitro.
Alveolar macrophages (AMs) play a central role in pulmonary inflammation in response to local stimuli. As a model for investigating anti-inflammatory drugs, we studied the effects of the cyclohexadepsipeptide antibiotic, fusafungine, and that of the glucocorticoid dexamethasone on the expression of ICAM-1, TNF-alpha and RANTES, induced in vitro by rIFN-gamma in human AMs freshly isolated from bronchoalveolar lavage fluid (BAL) obtained in lung-transplanted patients. ICAM-1 antigen expression, induced on AMs after 24 h of culture, was significantly inhibited by fusafungine in a concentration-dependent manner, as measured by flow cytometry analysis using an anti-CD54 monoclonal antibody. TNF-alpha production, but not RANTES release (measured by ELISA), was significantly inhibited. mRNA studies, by means of polymerase chain reaction amplification of complementary deoxyribonucleic acids (RT-PCR), showed no significant modification of mRNA levels, suggesting that fusafungine acts mainly at a post-transcriptional level. In the same conditions, dexamethasone significantly inhibited the release both of TNF-alpha and RANTES by AMs, mainly acting at the mRNA level, but had no effect on ICAM-1 expression. Assessment of the cellular and molecular targets of anti-inflammatory drugs in this model of human AM activation should lead to more appropriate treatment of inflammatory process of the respiratory tract. By virtue of its anti-inflammatory effects on alveolar macrophages, combined with its antibacterial properties, fusafungine should prove particularly suitable for local treatment of bacterial infections of the respiratory tract.
Fattal-German
M
M
Laboratory of Immunology CNRS ERS 566, Université Paris-XI, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France. sfattal@ccml.com
Le Roy Ladurie
F
F
Cerrina
J
J
Lecerf
F
F
Berrih-Aknin
S
S
D000336:Aerosols / Q000494:pharmacology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000235:genetics; D047630:Depsipeptides; D003907:Dexamethasone / Q000494:pharmacology; D005670:Fusarium; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D016040:Lung Transplantation / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology*; D011994:Recombinant Proteins; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D000336:Aerosols; D018946:Chemokine CCL5; D047630:Depsipeptides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C014001:fusafungin; D003907:Dexamethasone; D007371:Interferon-gamma