title: Hypoxia enhances the proliferative response of macrophages to CSF-1 and their pro-survival response to TNF.
abstract: 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.
authors.affiliation: Arthritis and Inflammation Research Centre, University of Melbourne Department of Medicine, The Royal Melbourne Hospital Parkville, Victoria, Australia. jahami@unimelb.edu.au
authors.forename: John A
authors.initials: JA
authors.lastname: Hamilton
authors.forename: Derek C
authors.initials: DC
authors.lastname: Lacey
authors.forename: Amanda
authors.initials: A
authors.lastname: Turner
authors.forename: Bernard
authors.initials: B
authors.lastname: de Kok
authors.forename: Jennifer
authors.initials: J
authors.lastname: Huynh
authors.forename: Glen M
authors.initials: GM
authors.lastname: Scholz
mesh_terms: D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D016173:Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016186:Receptor, Macrophage Colony-Stimulating Factor; D014409:Tumor Necrosis Factor-alpha