Open AccessHypoxia Enhances the Proliferative Response of Macrophages to CSF-1 and Their Pro-Survival Response to TNF
Author(s) -
John A. Hamilton,
Derek Lacey,
Amanda Turner,
Bernard de Kok,
Jennifer Huynh,
Glen M. Scholz
Publication year - 2012
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0045853
Subject(s) - hypoxia (environmental) , inflammation , monocyte , macrophage , cytokine , tumor necrosis factor alpha , protein kinase b , mapk/erk pathway , pi3k/akt/mtor pathway , immunology , p38 mitogen activated protein kinases , cancer research , biology , chemistry , medicine , kinase , microbiology and biotechnology , signal transduction , in vitro , biochemistry , oxygen , organic chemistry
In chronic inflammatory lesions there are increased numbers of macrophages with a possible contribution of enhanced survival/proliferation due, for example, to cytokine action; such lesions are often hypoxic. Prior studies have found that culture in low oxygen can promote monocyte/macrophage survival. We show here, using pharmacologic inhibitors, that the hypoxia-induced pro-survival response of macrophages exhibits a dependence on PI3-kinase and mTOR activities but surprisingly is suppressed by Akt and p38 MAPK activities. It was also found that in hypoxia at CSF-1 concentrations, which under normoxic conditions are suboptimal for macrophage proliferation, macrophages can proliferate more strongly with no evidence for alteration in CSF-1 receptor degradation kinetics. TNF promoted macrophage survival in normoxic conditions with an additive effect in hypoxia. The enhanced hypoxia-dependent survival and/or proliferation of macrophages in the presence of CSF-1 or TNF may contribute to their elevated numbers at a site of chronic inflammation.