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Blood, 1 December 2000, Vol. 96, No. 12, pp. 3857-3865
IMMUNOBIOLOGY
5-lipoxygenase expression in dendritic cells generated from
CD34+ hematopoietic progenitors and in lymphoid
organs
Rainer Spanbroek,
Markus Hildner,
Dieter Steinhilber,
Norbert Fusenig,
Kozo Yoneda,
Olof Rådmark, Bengt Samuelsson, and
Andreas J.R. Habenicht
From the Center for Vascular Medicine,
Friedrich Schiller University of Jena, Erfurt, Germany; the Department
of Pharmaceutical Chemistry, University of Frankfurt, Frankfurt,
Germany; the Division of Carcinogenesis and Differentiation, German
Cancer Research Center, Heidelberg, Germany; the Department of
Dermatology, Faculty of Medicine, Kyoto University, Kyoto, Japan; and
the Department of Medical Biochemistry and Biophysics, Division of
Chemistry II, Karolinska Institutet, Stockholm, Sweden.
The 5-lipoxygenase (5-LO) pathway in human
CD34+ hematopoietic progenitor cells, which were induced to
differentiate into dendritic cells (DCs) by cytokines in vitro and in
DCs of lymphoid tissues in situ, was examined. Extracts prepared from
HPCs contained low levels of 5-LO or 5-LO-activating protein.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) plus tumor
necrosis factor- (TNF- ) promoted DC differentiation and induced
a strong rise in 5-LO and FLAP expression. Fluorescence-activated cell
sorter (FACS) analyses identified a major DC population coexpressing human leukocyte antigen (HLA)-DR/CD80 and monocytic or Langerhans cell
markers. Transforming growth factor- 1 (TGF- -1), added to support DC maturation, strongly promoted the appearance of
CD1a+/Lag+ Langerhans-type cells as well as
mature CD83+ DCs. TGF- -1 further increased 5-LO and
FLAP expression, recruited additional cells into the 5-LO+
DC population, and promoted production of
5-hydroxyeicosatetraenoic acid and leukotriene B4 in
response to calcium (Ca++) ionophore A23187. These
in vitro findings were corroborated by 5-LO expression in distinct DC
phenotypes in vivo. Scattered 5-LO and FLAP in situ hybridization
signals were recorded in cells of paracortical T-lymphocyte-rich areas
and germinal centers (GCs) of lymph nodes (LNs) 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 have the unique ability to initiate
naive lymphocyte activation, our data support the hypothesis that
leukotrienes act at proximal steps of adaptive immune responses.

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