title: Hypoxia stimulus: An adaptive immune response during dendritic cell maturation.
abstract: The 'injury hypothesis' in organ transplantation suggests that ischemia-reperfusion injury is involved in the adaptative alloimmune response. We previously found that a strong immune/inflammatory response was induced by ischemia during kidney transplantation in rats. We show here that immature dendritic cells (DCs) undergo hypoxia-mediated differentiation comparable to allogeneic stimulation. Hypoxia-differentiated DCs overexpress hypoxia inducible factor-1alpha (HIF-1alpha) and its downstream target genes, such as vascular endothelial growth factor or glucose transporter-1. Rapamycin attenuated DC differentiation, HIF-1alpha expression, and its target gene expression in a dose-dependent manner along with downregulated interleukin-10 secretion. Coculture of hypoxia-differentiated DCs with CD3 lymphocytes induced proliferation of lymphocytes, a process also neutralized by rapamycin. Furthermore, in vivo examination of ischemia-reperfusion-injured mouse kidneys showed a clear maturation of resident DCs that was blunted by rapamycin pretreatment. Our results suggest that hypoxia is a central part of the 'injury hypothesis' triggering DC differentiation under hypoxic conditions. Rapamycin attenuates the hypoxic immune-inflammatory response through inhibition of the HIF-1alpha pathway.
authors.affiliation: Experimental Laboratory of Nephrology and Department of Nephrology, Ciutat Sanitaria i Universitaria de Bellvitge, IDIBELL, Barcelona, Spain. 33981ira@comb.es
authors.forename: I
authors.initials: I
authors.lastname: Rama
authors.forename: B
authors.initials: B
authors.lastname: Bruene
authors.forename: J
authors.initials: J
authors.lastname: Torras
authors.forename: R
authors.initials: R
authors.lastname: Koehl
authors.forename: J M
authors.initials: JM
authors.lastname: Cruzado
authors.forename: O
authors.initials: O
authors.lastname: Bestard
authors.forename: M
authors.initials: M
authors.lastname: Franquesa
authors.forename: N
authors.initials: N
authors.lastname: Lloberas
authors.forename: A
authors.initials: A
authors.lastname: Weigert
authors.forename: I
authors.initials: I
authors.lastname: Herrero-Fresneda
authors.forename: O
authors.initials: O
authors.lastname: Gulias
authors.forename: J M
authors.initials: JM
authors.lastname: Grinyó
mesh_terms: D000917:Antibody Formation / Q000187:drug effects; D002454:Cell Differentiation; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D020123:Sirolimus / Q000494:pharmacology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020123:Sirolimus