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1.
Clin Exp Immunol ; 149(3): 543-52, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17645766

ABSTRACT

Dendritic cell (DC) maturation may accelerate autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, and may contribute to accelerated atherosclerosis seen in these patients. The immune system responds to both exogenous and endogenous 'dangerous' signals that can induce dendritic cell maturation. We have found that autologous plasma contains danger signals that induce up-regulation of major histocompatibility complex (MHC) class II and co-stimulatory molecules in immature DCs (iDCs). The objective of this study was to determine whether low-density lipoprotein (LDL) and/or oxidized LDL (oxLDL) constitute danger signals, and to assess the effect of exposure to LDL and oxLDL following monocyte differentiation into iDCs in lipoprotein-deficient serum (LPDS). IDCs were generated in the presence of autologous plasma or LPDS. Expression of maturation and migration molecules was evaluated using flow cytometry, and morphology was assessed by light microscopy. Pro- or anti-apoptotic effect was determined using annexin V and propidium iodide binding. Phagocytosis of apoptotic cells was evaluated using autologous plasma or LPDS. LDL and oxLDL were clearly able to slightly up-regulate levels of HLA-DR and co-stimulatory molecule CD86. High oxLDL concentrations (50-100 microg/ml) were associated with expression of additional maturation molecules. Moreover, iDCs that were prepared in LPDS showed partial maturation following exposure to LDL and oxLDL, and improved tolerogenic apoptotic cell uptake. This study suggests that oxLDL, and to some extent LDL, are at least partly responsible for the iDC 'danger' response induced by autologous plasma.


Subject(s)
Dendritic Cells/drug effects , Lipoproteins, LDL/pharmacology , Antigens, CD/blood , Apoptosis/drug effects , B7-2 Antigen/blood , Cell Differentiation/drug effects , Cell Differentiation/immunology , Cells, Cultured , HLA-DR Antigens/blood , Humans , Immunoglobulins/blood , Membrane Glycoproteins/blood , Phagocytosis/immunology , Receptors, CCR7 , Receptors, Chemokine/blood , CD83 Antigen
2.
Oncogene ; 25(18): 2601-14, 2006 Apr 27.
Article in English | MEDLINE | ID: mdl-16434974

ABSTRACT

In order to obtain a comprehensive picture of the molecular events regulating cutaneous photodamage of intact human epidermis, suction blister roofs obtained after a single dose of in vivo ultraviolet (UV)B exposure were used for microarray profiling. We found a changed expression of 619 genes. Half of the UVB-regulated genes had returned to pre-exposure baseline levels at 72 h, underscoring the transient character of the molecular cutaneous UVB response. Of special interest was our finding that several of the central p53 target genes remained unaffected following UVB exposure in spite of p53 protein accumulation. We next compared the in vivo expression profiles of epidermal sheets to that of cultured human epidermal keratinocytes exposed to UVB in vitro. We found 1931 genes that differed in their expression profiles between the two groups. The expression profile in intact epidemis was geared mainly towards DNA repair, whereas cultured keratinocytes responded predominantly by activating genes associated with cell-cycle arrest and apoptosis. These differences in expression profiles might reflect differences between mature differentiating keratinocytes in the suprabasal epidermal layers versus exponentially proliferating keratinocytes in cell culture. Our findings show that extreme care should be taken when extrapolating from findings based on keratinocyte cultures to changes in intact epidermis.


Subject(s)
Biomarkers/metabolism , Epidermis/radiation effects , Gene Expression Profiling , Gene Expression Regulation/radiation effects , Keratinocytes/radiation effects , Ultraviolet Rays , Adult , Apoptosis/radiation effects , Cells, Cultured , DNA Repair/radiation effects , Epidermis/metabolism , Humans , Keratinocytes/metabolism , Oligonucleotide Array Sequence Analysis
3.
Apoptosis ; 10(5): 1009-18, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16151636

ABSTRACT

UNLABELLED: A number of mechanisms have been proposed to explain the etiology of drug-induced lupus (DIL) but the effect of apoptotic and necrotic cell handling has not been previously examined. OBJECTIVE: To evaluate the effect of quinidine and procainamide at therapeutic range concentrations, on the uptake of apoptotic and necrotic thymocytes by murine peritoneal macrophages and on macrophage survival, as a novel mechanism for DIL. METHODS: Thymocytes were stained and induced to undergo apoptosis by serum withdrawal. Apoptosis was evaluated using annexin V and propidum iodide (PI) and PI staining. Necrosis was induced by heating. Peritoneal macrophages were treated with quinidine or procainamide at a range of therapeutic concentrations and incubated with stained apoptotic and necrotic thymocytes. Apoptotic and necrotic cell uptake was evaluated by flow cytometry using double staining of thymocytes and macrophages and by confocal microscopy. Green fluorescent latex beads were used as controls for phagocytosis. RESULTS: Significantly decreased uptake of apoptotic and necrotic cells was seen in the presence of quinidine and procainamide. The documented effect was mainly on the number of apoptotic/necrotic cells per macrophage. Uptake of fluorescent latex beads offered to resident macrophages was not significantly affected by quinidine or procainamide. No pro-apoptotic effect of quinidine or procainamide on macrophages was seen. CONCLUSION: Quinidine and procainamide at therapeutic range concentrations specifically inhibit clearance of apoptotic and necrotic cells by peritoneal macrophages. Altered handling of apoptotic and necrotic cells may represent a contributing mechanism for DIL.


Subject(s)
Apoptosis/drug effects , Lupus Erythematosus, Systemic/chemically induced , Macrophages, Peritoneal/physiology , Phagocytosis/drug effects , Procainamide/pharmacology , Quinidine/pharmacology , Animals , Flow Cytometry , Macrophages, Peritoneal/drug effects , Mice , Mice, Inbred C57BL , Microspheres , Necrosis , T-Lymphocytes/cytology
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