Nicotine strongly activates dendritic cell-mediated adaptive immunity: potential role for progression of atherosclerotic lesions.
BACKGROUND
Antigen-presenting cells (APCs) such as monocytes and dendritic cells (DCs) stimulate T-cell proliferation and activation in the course of adaptive immunity. This cellular interaction plays a role in the growth of atherosclerotic plaques. Nicotine has been shown to increase the growth of atherosclerotic lesions. Therefore, we investigated whether nicotine can stimulate APCs and their T cell-stimulatory capacity using human monocyte-derived DCs and murine bone marrow-derived DCs as APCs.


RESULTS
Nicotine dose-dependently (10(-8) to 10(-4) mol/L) induced DC expression of costimulatory molecules (ie, CD86, CD40), MHC class II, and adhesion molecules (ie, LFA-1, CD54). Moreover, nicotine induced a 7.0-fold increase in secretion of the proinflammatory T(H)1 cytokine interleukin-12 by human DCs. These effects were abrogated by the nicotinic receptor antagonist alpha-bungarotoxin and mecamylamine, respectively. The effects of nicotine were mediated in part by the phosphorylation of the PI3 kinase downstream target Akt and the mitogen-activated kinases ERK and p38 MAPK. Nicotine-stimulated APCs had a greater capacity to stimulate T-cell proliferation and cytokine secretion, as documented by mixed lymphocyte reactions and ovalbumin-specific assays with ovalbumin-transgenic DO10.11 mice. In a murine model of atherosclerosis, nicotine significantly enhanced the recruitment of DCs to atherosclerotic lesions in vivo.


CONCLUSIONS
Nicotine activates DCs and augments their capacity to stimulate T-cell proliferation and cytokine secretion. These effects of nicotine may contribute to its influence on the progression of atherosclerotic lesions.
Aicher
Alexandra
A
Department of Internal Medicine IV, Molecular Cardiology, University of Frankfurt, Germany.
Heeschen
Christopher
C
Mohaupt
Mariette
M
Cooke
John P
JP
Zeiher
Andreas M
AM
Dimmeler
Stefanie
S
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001161:Arteriosclerosis / Q000276:immunology* / Q000473:pathology; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000096:biosynthesis; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects* / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
D015703:Antigens, CD; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D015815:Cell Adhesion Molecules; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D011978:Receptors, Nicotinic; D018664:Interleukin-12; D009538:Nicotine; D010047:Ovalbumin; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases