TY - JOUR
T1 - Hypoxia stimulus
T2 - An adaptive immune response during dendritic cell maturation
AU - Rama, I.
AU - Bruene, B.
AU - Torras, J.
AU - Koehl, R.
AU - Cruzado, J. M.
AU - Bestard, O.
AU - Franquesa, M.
AU - Lloberas, N.
AU - Weigert, A.
AU - Herrero-Fresneda, I.
AU - Gulias, O.
AU - Grinyó, J. M.
PY - 2008/4
Y1 - 2008/4
N2 - 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-1α (HIF-1α) and its downstream target genes, such as vascular endothelial growth factor or glucose transporter-1. Rapamycin attenuated DC differentiation, HIF-1α 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-1α pathway.
AB - 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-1α (HIF-1α) and its downstream target genes, such as vascular endothelial growth factor or glucose transporter-1. Rapamycin attenuated DC differentiation, HIF-1α 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-1α pathway.
KW - Costimulatory molecules
KW - Cytokines
KW - Dendritic cells
KW - Hypoxia
KW - mTOR inhibitors
UR - https://www.scopus.com/pages/publications/40849124059
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000254085100008&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1038/sj.ki.5002792
DO - 10.1038/sj.ki.5002792
M3 - Article
C2 - 18216782
AN - SCOPUS:40849124059
SN - 0085-2538
VL - 73
SP - 816
EP - 825
JO - Kidney International
JF - Kidney International
IS - 7
ER -