Hypoxia stimulus: An adaptive immune response during dendritic cell maturation

I. Rama; B. Bruene; J. Torras; R. Koehl; J. M. Cruzado; O. Bestard; M. Franquesa; N. Lloberas; A. Weigert; I. Herrero-Fresneda; O. Gulias; J. M. Grinyó

doi:10.1038/sj.ki.5002792

Hypoxia stimulus: An adaptive immune response during dendritic cell maturation

I. Rama^*, B. Bruene, J. Torras, R. Koehl, J. M. Cruzado, O. Bestard, M. Franquesa, N. Lloberas, A. Weigert, I. Herrero-Fresneda, O. Gulias, J. M. Grinyó

^*Corresponding author for this work

Research output: Indexed journal article › Article › peer-review

66 Citations (Scopus)

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-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.

Original language	English
Pages (from-to)	816-825
Number of pages	10
Journal	Kidney International
Volume	73
Issue number	7
DOIs	https://doi.org/10.1038/sj.ki.5002792
Publication status	Published - Apr 2008
Externally published	Yes

Keywords

Costimulatory molecules
Cytokines
Dendritic cells
Hypoxia
mTOR inhibitors

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10.1038/sj.ki.5002792

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@article{19ab5c54f24b4b41b2cb4987ad2fd2d7,

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-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.",

keywords = "Costimulatory molecules, Cytokines, Dendritic cells, Hypoxia, mTOR inhibitors",

author = "I. Rama and B. Bruene and J. Torras and R. Koehl and Cruzado, {J. M.} and O. Bestard and M. Franquesa and N. Lloberas and A. Weigert and I. Herrero-Fresneda and O. Gulias and Griny{\'o}, {J. M.}",

note = "Funding Information: We are indebted to Elke Dauber, Sabine Oldendorf, and Sandra Christmann for their technical contribution. We appreciate Tobias Schmid for his scientific collaboration and Dr Ram{\'o}n Vilella for his pivotal role in dendritic cell isolation. This research was supported by ISCIII/FIS (PI03/0082), ISCIII/FIS (PI05/1049), ISCIII/FIS (PI06/0067), and MEC (SAF2004-04705). N{\'u}ria Lloberas is a researcher from Transplant Network. Marcel.la Franquesa holds fellowships from Fundaci{\'o} Catalana de Trasplantament and from PROLIGEN in the FP6-2005-LIFESCIHEALTH-7. Immaculada Herrero-Fresneda, Nuria Lloberas, and In{\'e}s Rama are researchers from ISCIII/FIS.",

year = "2008",

month = apr,

doi = "10.1038/sj.ki.5002792",

language = "English",

volume = "73",

pages = "816--825",

journal = "Kidney International",

issn = "0085-2538",

publisher = "Elsevier B.V.",

number = "7",

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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.

N1 - Funding Information: We are indebted to Elke Dauber, Sabine Oldendorf, and Sandra Christmann for their technical contribution. We appreciate Tobias Schmid for his scientific collaboration and Dr Ramón Vilella for his pivotal role in dendritic cell isolation. This research was supported by ISCIII/FIS (PI03/0082), ISCIII/FIS (PI05/1049), ISCIII/FIS (PI06/0067), and MEC (SAF2004-04705). Núria Lloberas is a researcher from Transplant Network. Marcel.la Franquesa holds fellowships from Fundació Catalana de Trasplantament and from PROLIGEN in the FP6-2005-LIFESCIHEALTH-7. Immaculada Herrero-Fresneda, Nuria Lloberas, and Inés Rama are researchers from ISCIII/FIS.

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 - http://www.scopus.com/inward/record.url?scp=40849124059&partnerID=8YFLogxK

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 -

Hypoxia stimulus: An adaptive immune response during dendritic cell maturation

Abstract

Keywords

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