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Pentoxifylline suppresses CD14 positive monocyte derived dendritic cell differentiation, maturation and functions
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ASSOCIATION FOR ACADEMIC SURGERY AND SOCIETY OF UNIVERSITY SURGEONS—ABSTRACTS
abrogate recurrent autoimmune destruction of islet grafts transplanted into diabetic recipients. These data suggest that the mechanism of autoimmune abrogation mediated by T cell depletion and donor PLNC operates through induction of autoantigen-induced IL-4 secretion.
208. PENTOXIFYLLINE SUPPRESSES CD14 POSITIVE MONOCYTE DERIVED DENDRITIC CELL DIFFERENTIATION, MATURATION AND FUNCTIONS. R. Zhang, U. Bharadwaj, M. Li, C. Chen, Q. Yao; Baylor College of Medicine, Houston, TX. Introduction: Pentoxifylline (PTX) is a methylxanthine derivative that inhibits phosphodiesterase activity, induces vasodilation, and blocks the effect of TNF-␣. Currently, PTX is a commonly used drug for tissue ischemia and other inflammatory conditions. Although its immunomudulation property has been recognized, the effect of PTX on dendritic cells (DCs), the most efficient antigenpresenting cells, is unknown. The present work aimed at determining whether PTX could suppress DC differentiation, maturation, and its associated functions. Methods: CD14⫹ monocytes were isolated from human PBMC by using CD14⫹ MACS magnetic beads. The cells were then cultured with GM-CSF and IL-4 for 5 days to generate immature DCs (iDCs), and further treated with lipopolysachraride (LPS) for an additional 2 days for mature DCs (mDCs). PTX was added to the culture during DC differentiation and maturation. Cell surface markers were analyzed by flow cytometry. Endocytosis activity was determined by the efficiency of FITC-dextran uptake. DC secreted cytokines were determined by bio-plex cytokine assay. Antigen-presentation function was determined by mixed lymphocyte reaction (MLR). Results: Through cellular marker analysis, PTX showed an inhibitory effect on DC differentiation in a dosedependent fashion (5, 50, and 300 g/ml) PTX treatment significantly down-regulated the expression of CD54, CD80, CD86 and HLA-DR in fully differentiated iDCs. In addition, PTX downregulated the expression of those molecules plus DC maturation marker CD83 after DC maturation by LPS. Furthermore, PTX inhibited antigen-uptake of DCs when tested by FITC-dextran. Among cytokines secreted from activated DCs, the production of TNF-␣ and IFN-␥ was significantly decreased in the presence of PTX treatment. Consequently, PTX-treated DCs exerted an inhibitory effect on T cell allostimulatory activity in MLR. Conclusions: PTX significantly inhibits CD14⫹ monocyte-derived DC differentiation and activation, iDC antigen-uptake and mDC antigen-presentation ability. These alterations of DCs may be mediated by PTX-induced downregulation of TNF-␣ and IFN- ␥ production. This study suggests a novel effect of PTX on the immune system, which may have new clinical applications.
ASSOCIATION FOR ACADEMIC SURGERY AND SOCIETY OF UNIVERSITY SURGEONS—ABSTRACTS
abrogate recurrent autoimmune destruction of islet grafts transplanted into diabetic recipients. These data suggest that the mechanism of autoimmune abrogation mediated by T cell depletion and donor PLNC operates through induction of autoantigen-induced IL-4 secretion.
208. PENTOXIFYLLINE SUPPRESSES CD14 POSITIVE MONOCYTE DERIVED DENDRITIC CELL DIFFERENTIATION, MATURATION AND FUNCTIONS. R. Zhang, U. Bharadwaj, M. Li, C. Chen, Q. Yao; Baylor College of Medicine, Houston, TX. Introduction: Pentoxifylline (PTX) is a methylxanthine derivative that inhibits phosphodiesterase activity, induces vasodilation, and blocks the effect of TNF-␣. Currently, PTX is a commonly used drug for tissue ischemia and other inflammatory conditions. Although its immunomudulation property has been recognized, the effect of PTX on dendritic cells (DCs), the most efficient antigenpresenting cells, is unknown. The present work aimed at determining whether PTX could suppress DC differentiation, maturation, and its associated functions. Methods: CD14⫹ monocytes were isolated from human PBMC by using CD14⫹ MACS magnetic beads. The cells were then cultured with GM-CSF and IL-4 for 5 days to generate immature DCs (iDCs), and further treated with lipopolysachraride (LPS) for an additional 2 days for mature DCs (mDCs). PTX was added to the culture during DC differentiation and maturation. Cell surface markers were analyzed by flow cytometry. Endocytosis activity was determined by the efficiency of FITC-dextran uptake. DC secreted cytokines were determined by bio-plex cytokine assay. Antigen-presentation function was determined by mixed lymphocyte reaction (MLR). Results: Through cellular marker analysis, PTX showed an inhibitory effect on DC differentiation in a dosedependent fashion (5, 50, and 300 g/ml) PTX treatment significantly down-regulated the expression of CD54, CD80, CD86 and HLA-DR in fully differentiated iDCs. In addition, PTX downregulated the expression of those molecules plus DC maturation marker CD83 after DC maturation by LPS. Furthermore, PTX inhibited antigen-uptake of DCs when tested by FITC-dextran. Among cytokines secreted from activated DCs, the production of TNF-␣ and IFN-␥ was significantly decreased in the presence of PTX treatment. Consequently, PTX-treated DCs exerted an inhibitory effect on T cell allostimulatory activity in MLR. Conclusions: PTX significantly inhibits CD14⫹ monocyte-derived DC differentiation and activation, iDC antigen-uptake and mDC antigen-presentation ability. These alterations of DCs may be mediated by PTX-induced downregulation of TNF-␣ and IFN- ␥ production. This study suggests a novel effect of PTX on the immune system, which may have new clinical applications.