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Am J Physiol Cell Physiol 284: C439-C446, 2003. First published September 25, 2002; doi:10.1152/ajpcell.00294.2002
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Vol. 284, Issue 2, C439-C446, February 2003

NO and TNF-alpha released from activated macrophages stabilize HIF-1alpha in resting tubular LLC-PK1 cells

Jie Zhou1, Joachim Fandrey2, Jens Schümann3, Gisa Tiegs3, and Bernhard Brüne1

1 Department of Cell Biology, Faculty of Biology, University of Kaiserslautern, 67663 Kaiserslautern; 2 Institute of Physiology, Faculty of Medicine, University of Essen, 45122 Essen; and 3 Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Erlangen, 91054 Erlangen, Germany

Hypoxic/ischemic conditions provoke activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). HIF-1 is composed of HIF-1alpha (subjected to protein stability regulation) and constitutively expressed HIF-1beta . Besides hypoxia, diverse agonists are identified that stabilize HIF-1alpha during normoxia. Here we used a coculture system of RAW 264.7 macrophage cells and tubular LLC-PK1 cells to establish that lipopolysaccharide- and interferon-gamma -stimulated but not resting macrophages elicited HIF-1alpha accumulation in LLC-PK1 cells. Via pharmacological interventions such as blockade of nitric oxide (NO) production in macrophages, scavenging of NO with the use of 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, or application of tumor necrosis factor-alpha (TNF-alpha )-neutralizing antibodies, we identified NO and TNF-alpha as signaling molecules. Working in concert, NO and TNF-alpha have a stronger response when allowed direct cell-to-cell contact instead of contact with only the cell supernatant of activated macrophages. We show that signal transmission by NO with TNF-alpha in LLC-PK1 cells is mediated via the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, because it is blocked by wortmannin or dominant-negative forms of PI3-K as well as protein kinase B. We conclude that NO and TNF-alpha , derived from activated macrophages, provoke HIF-1alpha stabilization in LLC-PK1 cells under normoxic conditions, which underscores HIF-1alpha stabilization due to intercellular regulation.

nitric oxide; tumor necrosis factor-alpha ; hypoxia-inducible factor-1; intercellular signaling; phosphatidylinositol 3-kinase; cytokine; Akt


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