Hypoxia modulates expression of the 70-kD heat shock protein and reduces Leishmania infection in macrophages.

Department of Parasitology, Biology Institute, Universidade Estadual de Campinas, Campinas, SP, Brazil.
Journal of Biomedical Science (Impact Factor: 2.46). 10/2004; 11(6):847-54. DOI:10.1159/000081832
Source: PubMed

ABSTRACT Hypoxia, a microenvironmental factor present in diseased tissues, has been recognized as a specific metabolic stimulus or a signal of cellular response. Experimental hypoxia has been reported to induce adaptation in macrophages such as differential migration, elevation of proinflammatory cytokines and glycolytic enzyme activities, and decreased phagocytosis of inert particles. In this study we demonstrate that although exposure to hypoxia (5% O2, 5% CO2, and balanced N2) did not change macrophage viability, or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cleavage and proliferation, it significantly reduced expression of the 70-kD heat shock protein (HSP70), which was restored to prehypoxia levels after reoxygenation. The influence of low oxygen tension on macrophage functional activity was also studied, i.e. the ability of these cells to maintain or resist infection by a microorganism. We demonstrate that macrophages from two different sources (a murine cell line and primary cells) exposed to hypoxia were efficiently infected with Leishmania amazonensis, but after 24 h showed a reduction in the percentage of infected cells and of the number of intracellular parasites per macrophage, indicating that hypoxia induced macrophages to kill the intracellular parasites. These results support the notion that hypoxia, a microenvironmental factor, can modulate macrophage protein expression and functional activity.

0 0
  • [show abstract] [hide abstract]
    ABSTRACT: Macrophages are among the oldest cell types in the animal kingdom, and they have a long evolutionary history and experience various evolutionary pressures. It was clear from the earliest studies that variations exist in macrophage populations. Macrophages are known to adapt to their microenvironment. Although the paradigm for macrophage plasticity is their flexible program driven by environmental signals, the most common working hypothesis is that of a dichotomy between two major macrophage phenotypes, M1 and M2. A PubMed and Web of Science databases search was performed providing evidences that numerous authors have expanded the concept of plasticity and conducted experimental studies focusing on the complex program of phenotypes. This review evaluated a number of issues relating to macrophage plasticity, environmental heterogeneity and the potential for changes to be reversal or non reversal in an ecological context. The ecological principles of phenotypic plasticity which can assist in evaluating and interpreting macrophage experimental data are discussed as well.
    Agents and Actions 07/2013; · 1.59 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Hypoxia (low oxygen tension) is a common feature of inflamed and infected tissues. The influence of hypoxia on macrophage responses to micro-organisms has only recently been studied. This study demonstrates that hypoxia induced macrophages to control Leishmania amazonensis, an intracellular parasite that causes cutaneous and cutaneous metastatic lesions. The mechanisms that contribute to the control of macrophages against L. amazonensis infection under a hypoxic microenvironment are not known. Nitric oxide, TNF-α, IL-10 or IL-12 is not responsible for the decrease in parasitism under hypoxia. Live L. amazonensis entry or exocytosis of internalized particles as well as energetic metabolism was not impaired in infected macrophages; no apoptosis-like death was detected in intracellular parasites. Reactive oxygen species (ROS) is likely to be involved, because treatment with antioxidants N-acetylcysteine (NAC) and ebselen inhibits the leishmanicidal effect of macrophages under hypoxia. Leishmania amazonensis infection induces macrophages to express hypoxia-inducible factor-1 (HIF-1α) and -2 (HIF-2α). Data indicate that hypoxia affects the microbial activities and protein expression of macrophages leading to a different phenotype from that of the normoxic counterpart and that it plays a role in modulating Leishmania infection.
    Scandinavian Journal of Immunology 04/2011; 74(2):165-75. · 2.20 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Development of hypoxic areas occurs during infectious and inflammatory processes and dendritic cells (DCs) are involved in both innate and adaptive immunity in diseased tissues. Our group previously reported that macrophages exposed to hypoxia were infected with the intracellular parasite Leishmania amazonensis, but showed reduced susceptibility to the parasite. This study shows that although hypoxia did not alter human DC viability, it significantly altered phenotypic and functional characteristics. The expression of CD1a, CD80, and CD86 was significantly reduced in DCs exposed to hypoxia, whereas CD11c, CD14, CD123, CD49 and HLA-DR expression remained unaltered in DCs cultured in hypoxia or normoxia. DC secretion of IL-12p70, the bioactive interleukin-12 (IL-12), a cytokine produced in response to inflammatory mediators, was enhanced under hypoxia. In addition, phagocytic activity (Leishmania uptake) was not impaired under hypoxia, although this microenviroment induced infected DCs to reduce parasite survival, consequently controlling the infection rate. All these data support the notion that a hypoxic microenvironment promotes selective pressure on DCs to assume a phenotype characterized by pro-inflammatory and microbial activities in injured or inflamed tissues and contribute to the innate immune response.
    Apmis 02/2010; 118(2):108-14. · 2.07 Impact Factor