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Am J Physiol Cell Physiol (September 25, 2002). doi:10.1152/ajpcell.00294.2002
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Articles in PresS, published online ahead of print September 25, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00294.2002
Submitted on June 25, 2002
Accepted on September 20, 2002

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

Jie Zhou1, Joachim Fandrey2, Jens Schumann3, Gisa Tiegs3, and Bernhard Brune1*

1 Cell Biology, University of Kaiserslautern, Kaiserslautern, Germany
2 Physiology, University of Essen, Essen, Germany
3 Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuernberg, Erlangen, Germany

* To whom correspondence should be addressed. E-mail: bruene{at}rhrk.uni-kl.de.

Hypoxic/ischemic conditions provoke activation of the transcription factor hypoxia inducible factor-1 (HIF-1). HIF-1 is composed of HIF-1{alpha}, subjected to protein stability regulation, and constitutively expressed HIF-1ß. Besides hypoxia, diverse agonists are identified to stabilize HIF-1{alpha} during normoxia. Here we used a co-culture system of RAW264.7 macrophage cells and tubular LLC-PK1 cells to establish that lipopolysaccharide/interferon-{gamma} stimulated, but not resting macrophages elicited HIF-1{alpha} accumulation in LLC-PK1 cells. By pharmacological interventions such as blocking NO production in macrophages, scavenging NO with the use of carboxy-PTIO, or application of TNF{alpha} neutralizing antibodies, we identified nitric oxide (NO) and tumor necrosis factor-{alpha} (TNF{alpha}) as signaling molecules. NO and TNF{alpha} work in concert with a stronger response when allowing direct cell-cell contacts instead of working with the cell supernatant of activated macrophages, only. Signal transmission by NO/TNF{alpha} in LLC-PK1 cells is mediated via the phosphotidylinositol-3-kinase/AKT pathway because it is blocked by wortmannin or dominant-negative forms of the phosphotidylinositol-3-kinase as well as PKB. We conclude that NO and TNF{alpha}, derived form activated macrophages, provoke HIF-1{alpha} stabilization in LLC-PK1 cells under normoxic conditions which underscores HIF-1{alpha} stabilization due to intercellular regulation.




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