Cigarette smoke differentially modulates dendritic cell maturation and function in time.
BACKGROUND
Dendritic cells (DCs) as professional antigen presenting cells (APCs) play a critical role in the regulation of host immune responses. DCs evolve from immature, antigen-capturing cells, to mature antigen-presenting cells. The relative contribution of DCs to cigarette smoke-induced inflammation is not well documented. In the current study, we investigated a modulatory effect of cigarette smoke extract (CSE) on differentiation, maturation and function of DCs.


METHODS
Primary murine DCs were grown from bone marrow cells with GM-CSF. Development of DC was analyzed by expression of CD11c, MHCII, CD86, CD40 and CD83 using flow cytometry. Murine DC's and human L428 cells were co-cultured with CSE for various periods of time. Functional activity was analyzed by measuring FITC-dextran uptake, cytokine production and the ability to stimulate T cell activation in a mixed lymphocyte reaction.


RESULTS
Our results show that short-term CSE stimulation (~24 h) influence the maturation status of newly differentiated and immature DCs towards more mature cells as revealed by upregulation of MHCII, CD83, CD86, CD40, reduction in antigen up-take capacity and enhanced secretion of pro-inflammatory (IL-12, IL-6 and TNF-α) cytokines. Interestingly, long-term CSE exposure, time- and concentration-dependently, suppressed the development of functional DCs. This suppression was demonstrated by a decline in CD11c/MHCII, CD83, CD86 and CD40 expression, the production of cytokines and ability to stimulate T lymphocytes. Moreover, CSE significantly suppressed the endocytosis function of mouse DCs which was not due to diminished DC viability. Similar to mouse DCs, long-term co-culturing of the human L428 DC cell line with CSE time-dependently suppressed the expression of CD54.


CONCLUSIONS
The present study provides evidence that CSE modulates DC-mediated immune responses via affecting both the function and maturation of DCs. The suppressive effects of cigarette smoke on DC function might lead to impaired immune responses to various infections.
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO BOX 80082, 3508, TB, Utrecht, The Netherlands.|Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Shahid Chamran University, Ahvaz, Iran.
Masoumeh Ezzati
ME
Givi
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO BOX 80082, 3508, TB, Utrecht, The Netherlands.
Gert
G
Folkerts
Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands.
Gerry T M
GT
Wagenaar
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO BOX 80082, 3508, TB, Utrecht, The Netherlands. f.a.m.redegeld@uu.nl.
Frank A
FA
Redegeld
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO BOX 80082, 3508, TB, Utrecht, The Netherlands.|Chronic Respiratory Diseases Research Center and National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Department of Immunology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.|Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
Esmaeil
E
Mortaz
D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D010641:Phenotype; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D015415:Biomarkers; D016207:Cytokines; D012906:Smoke