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Updated: Aug 11, 2026
Functional Characterization of Regulatory Macrophages That Inhibit Graft-reactive Immunity
Published on: June 7, 2017
Expression and modulation of ICAM-1, TNF-alpha and RANTES in human alveolar macrophages from lung-transplant
M Fattal-German1, F Le Roy Ladurie, J Cerrina
1Laboratory of Immunology CNRS ERS 566, Université Paris-XI, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France. sfattal@ccml.com
Abstract:
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.
Insights
Fusafungine reduces inflammatory markers like ICAM-1 and TNF-alpha in human alveolar macrophages, suggesting post-transcriptional action. Dexamethasone also inhibits TNF-alpha and RANTES, primarily at the mRNA level.
Area of Science:
- Pulmonary immunology
- Pharmacology
Background:
- Alveolar macrophages (AMs) are key players in lung inflammation.
- Investigating anti-inflammatory drugs requires models of AM activation.
Purpose of the Study:
- To evaluate the effects of fusafungine and dexamethasone on inflammatory markers in human AMs.
- To elucidate the molecular mechanisms of action for these drugs.
Main Methods:
- Human AMs from lung transplant patients were stimulated with rIFN-gamma in vitro.
- Flow cytometry and ELISA were used to measure ICAM-1, TNF-alpha, and RANTES.
- RT-PCR analyzed mRNA levels to determine drug action at transcriptional or post-transcriptional levels.
Main Results:
- Fusafungine inhibited ICAM-1 expression and TNF-alpha production in a concentration-dependent manner, acting post-transcriptionally.
- Dexamethasone inhibited TNF-alpha and RANTES release, primarily at the mRNA level, with no effect on ICAM-1.
Conclusions:
- Fusafungine demonstrates anti-inflammatory effects on human AMs, particularly at the post-transcriptional level.
- Dexamethasone targets inflammatory mediators differently, mainly affecting mRNA expression.
- This model aids in understanding drug mechanisms for respiratory tract inflammatory conditions.
