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

被引:69
作者
Zhou, J
Fandrey, J
Schümann, J
Tiegs, G
Brüne, B
机构
[1] Univ Kaiserslautern, Dept Cell Biol, Fac Biol, D-67663 Kaiserslautern, Germany
[2] Univ Essen Gesamthsch, Inst Physiol, Fac Med, D-45122 Essen, Germany
[3] Univ Erlangen Nurnberg, Inst Expt & Clin Pharmacol & Toxicol, Fac Med, D-91054 Erlangen, Germany
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2003年 / 284卷 / 02期
关键词
nitric oxide; tumor necrosis factor-alpha; hypoxia-inducible factor-1; intercellular signaling; phosphatidylinositol; 3-kinase; cytokine; Akt;
D O I
10.1152/ajpcell.00294.2002
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:C439 / C446
页数:8
相关论文
共 44 条
[1]   HIF-1 expression in healing wounds:: HIF-1α induction in primary inflammatory cells by TNF-α [J].
Albina, JE ;
Mastrofrancesco, B ;
Vessella, JA ;
Louis, CA ;
Henry, WL ;
Reichner, JS .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2001, 281 (06) :C1971-C1977
[2]   Lack of evidence for the involvement of the phosphoinositide 3-kinase/Akt pathway in the activation of hypoxia-inducible factors by low oxygen tension [J].
Alvarez-Tejado, M ;
Alfranca, A ;
Aragonés, J ;
Vara, A ;
Landázuri, MO ;
del Peso, L .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (16) :13508-13517
[3]   Role of translocation in the activation and function of protein kinase B [J].
Andjelkovic, M ;
Alessi, DR ;
Meier, R ;
Fernandez, A ;
Lamb, NJC ;
Frech, M ;
Cron, P ;
Cohen, P ;
Lucocq, JM ;
Hemmings, BA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (50) :31515-31524
[4]   Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-1α nor sufficient for HIF-1-dependent target gene transcription [J].
Arsham, AM ;
Plas, DR ;
Thompson, CB ;
Simon, MC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (17) :15162-15170
[5]   Signal transduction by tumor necrosis factor and its relatives [J].
Baud, V ;
Karin, M .
TRENDS IN CELL BIOLOGY, 2001, 11 (09) :372-377
[6]   HIF-1-dependent transcriptional activity is required for oxygen-mediated HIF-1α degradation [J].
Berra, E ;
Richard, DE ;
Gothié, E ;
Pouysségur, J .
FEBS LETTERS, 2001, 491 (1-2) :85-90
[7]   Nitric oxide and the regulation of gene expression [J].
Bogdan, C .
TRENDS IN CELL BIOLOGY, 2001, 11 (02) :66-75
[8]   Transcription factors p53 and HIF-1α as targets of nitric oxide [J].
Brüne, B ;
von Knethen, A ;
Sandau, KB .
CELLULAR SIGNALLING, 2001, 13 (08) :525-533
[9]   Oxygen sensing and molecular adaptation to hypoxia [J].
Bunn, HF ;
Poyton, RO .
PHYSIOLOGICAL REVIEWS, 1996, 76 (03) :839-885
[10]  
Chen EY, 2001, CANCER RES, V61, P2429