5-lipoxygenase expression in dendritic cells generated from CD34(+) hematopoietic progenitors and in lymphoid organs

The 5-lipoxygenase (5-LO) pathway in human CD34(+) hematopoietic progenitor cells, which were induced to differentiate into dendritic cells (DCs) by c ytokines in vitro and in DCs of lymphoid tissues in situ, was examined, Ext racts prepared from HPCs contained low levels of 5-LO or 5-LO-activating pr otein. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plus tumor necrosis factor-alpha (TNF-alpha) promoted DC differentiation and induced a strong rise in 5-LO and FLAP expression. Fluorescence-activated cell sort er (FACS) analyses identified a major DC population coexpressing human leuk ocyte antigen (HLA)-DR/CD80 and monocytic or Langerhans cell markers, Trans forming growth factor-beta1 (TGF-beta -1), added to support DC maturation, strongly promoted the appearance of CD1a(+)/Lag(+) Langerhans-type cells as well as mature CD83(+) DCs, TGF-beta -1 further increased 5-LO and FLAP ex pression, recruited additional cells into the 5-LO+ DC population, and prom oted production of 5-hydroxyeicosatetraenoic acid and leukotriene Bq in res ponse to calcium (Ca++) ionophore A23187, These in vitro findings were corr oborated by 5-LO expression in distinct DC phenotypes in vivo. Scattered 5- LO and FLAP in situ hybridization signals were recorded in cells of paracor tical T-lymphocyte-rich areas and germinal centers (GCs) of lymph nodes (LN s) and tonsil and in cells of mucosae overlying the Waldeyer tonsillar ring . 5-LO protein localized to both CD1a(+) immature DCs and to CD83(+) mature interdigitating DCs of T-lymphocyte-rich areas of LNs and tonsil. As DCs h ave the unique ability to initiate naive lymphocyte activation, our data su pport the hypothesis that leukotrienes act at proximal steps of adaptive im mune responses. (C) 2000 by The American Society of Hematology.