Hypoxia modulates lipopolysaccharide induced TNF-alpha expression in murine macrophages.

Abstract

The pro-inflammatory activity of Tumor necrosis factor-alpha (TNF-alpha) together with tissue hypoxia determine the clinical outcome in sepsis and septic shock. p38 MAPKinase is the primary intracellular signaling pathway that regulates lipopolysaccharide (LPS)-induced TNF-alpha biosynthesis, however, the effect of hypoxia on LPS mediated activation of p38 is not known. Here we report that SB203580, a specific p38 MAPK inhibitor, which completely abolished LPS-induced TNF-alpha expression by the mouse macrophage cell RAW264.7 in normoxic conditions, lost the inhibitory effect in hypoxic conditions. Hypoxia did not modulate expression of p38 MAPK, but increased that of p-MK2, a downstream target of p38 MAPK. In LPS induced endotoxemia mice model SB203580 had no inhibitory effect on the serum levels of TNF-alpha. Furthermore, hypoxia inducible factor-1alpha (HIF-1alpha) was detected in vivo after LPS administration but its expression was not affected by SB203580. Our data indicate that LPS induced p38 MAPK activation was enhanced by hypoxia and consequently increased TNF-alpha secretion. Furthermore, the induction of HIF-1alpha in mice with endotoxemia suggested a synergistic effect on p38 mediated TNF-alpha expression. These findings provide new insights on the pathophysiological effects of hypoxia in sepsis and septic shock.

• Authors: Feng Qin Liu, Yan Liu, Vincent C H Lui, Jonathan R Lamb, Paul K H Tam, Yan Chen
• Journal: Experimental cell research (Exp Cell Res) Vol. 314 Issue 6 Pg. 1327-36 (Apr 01 2008) ISSN: 0014-4827 [Print] United States
• PMID: 18255061 (Publication Type: Journal Article)

Chemical References

• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Imidazoles
• Intracellular Signaling Peptides and Proteins
• Lipopolysaccharides
• Pyridines
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• Cobalt
• MAP-kinase-activated kinase 2
• Protein Serine-Threonine Kinases
• p38 Mitogen-Activated Protein Kinases
• cobaltous chloride
• SB 203580

Topics

• Animals
• Cell Hypoxia (drug effects)
• Cell Line
• Cobalt (pharmacology)
• Endotoxemia (blood, chemically induced)
• Enzyme Activation (drug effects)
• Gene Expression Regulation (drug effects)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Imidazoles (pharmacology)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Kinetics
• Lipopolysaccharides (pharmacology)
• Lung (drug effects, pathology)
• Macrophages (cytology, drug effects, enzymology)
• Mice
• Protein Serine-Threonine Kinases (metabolism)
• Pyridines (pharmacology)
• RNA Stability (drug effects)
• RNA, Messenger (genetics, metabolism)
• Transcription, Genetic (drug effects)
• Tumor Necrosis Factor-alpha (blood, genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)