Hypoxia stimulus: An adaptive immune response during dendritic cell maturation.
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.
Rama
I
I
Experimental Laboratory of Nephrology and Department of Nephrology, Ciutat Sanitaria i Universitaria de Bellvitge, IDIBELL, Barcelona, Spain. 33981ira@comb.es
Bruene
B
B
Torras
J
J
Koehl
R
R
Cruzado
J M
JM
Bestard
O
O
Franquesa
M
M
Lloberas
N
N
Weigert
A
A
Herrero-Fresneda
I
I
Gulias
O
O
Grinyó
J M
JM
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
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020123:Sirolimus