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Production through the HIF-1
Transcription Factor1
* Servicio de Inmunología, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid;
Gabinete Veterinario, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid;
Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
Low oxygen tension areas are found in inflamed or diseased tissues where hypoxic cells induce survival pathways by regulating the hypoxia-inducible transcription factor (HIF). Macrophages are essential regulators of inflammation and, therefore, we have analyzed their response to hypoxia. Murine peritoneal elicited macrophages cultured under hypoxia produced higher levels of IFN-
and IL-12 mRNA and protein than those cultured under normoxia. A similar IFN- increment was obtained with in vivo models using macrophages from mice exposed to atmospheric hypoxia. Our studies showed that IFN- induction was mediated through HIF-1
binding to its promoter on a new functional hypoxia response element. The requirement of HIF- in the IFN- induction was confirmed in RAW264.7 cells, where HIF-1 was knocked down, as well as in resident HIF-1 null macrophages. Moreover, Ag presentation capacity was enhanced in hypoxia through the up-regulation of costimulatory and Ag-presenting receptor expression. Hypoxic macrophages generated productive immune synapses with CD8 T cells that were more efficient for activation of TCR/CD3
, CD3
and linker for activation of T cell phosphorylation, and T cell cytokine production. In addition, hypoxic macrophages bound opsonized particles with a higher efficiency, increasing their phagocytic uptake, through the up-regulated expression of phagocytic receptors. These hypoxia-increased immune responses were markedly reduced in HIF-1- and in IFN--silenced macrophages, indicating a link between HIF-1 and IFN- in the functional responses of macrophages to hypoxia. Our data underscore an important role of hypoxia in the activation of macrophage cytokine production, Ag-presenting activity, and phagocytic activity due to an HIF-1-mediated increase in IFN- levels.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Migration and Inflammation Network UAMAD04 and Comision Interministerial de Ciencia y Tecnologia (to M.O.L.) and Red Temática de Enfermedades Cardiovasculares (RD06/0014/0031 to M.O.L., RD06/0014/0030 to F.S.-M., and fellowship for M.M.). B.A.-I. is an investigator from the Ministerio de Educación y Ciencia. A.E. is from the Ministerio de Salud y Consumo. I.M.O., M.J.C., and J.A. are investigators from the Ministerio de Ciencia y Tecnología Programa Ramón y Cajal.
2 B.A.-I., A.E., and I.M.O. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Manuel O. Landázuri, Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, C/ Diego de León, 62, E-28006, Madrid, Spain. E-mail address: mortiz.hlpr{at}salud.madrid.org
4 Abbreviations used in this paper: HIF, hypoxia-inducible factor; PHD, prolyl hydroxylase domain; VEGF, vascular endothelial growth factor; IS, immune synapse; MTOC, microtubule-organizing center; HRE, hypoxia response element; LAT, linker for activation of T cells; MHC-I/II, MHC class I/II; RT, real time; siRNA, small interfering RNA; ChIP, chromatin immunoprecipitation; siSCR, scrambled siRNA; OVAp, OVA peptide; Glut-1, glucose transporter type-1; DMOG, dimethyloxalylglycine.
5 The online version of this article contains supplemental material.
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