Attenuation of hypoxia-ischemia-induced monocyte chemoattractant protein-1 expression in brain of neonatal mice deficient in interleukin-1 converting enzyme.

Abstract

Interleukin-1beta (IL-1beta) upregulates expression of the chemokine monocyte chemoattractant protein-1 (MCP-1) in many experimental models. In neonatal rodent brain, hypoxia-ischemia rapidly stimulates expression of this chemokine, although the role of IL-1beta in regulating this response is unknown. Interleukin-1 converting enzyme (ICE) is a cysteine protease that cleaves inactive pro-IL-1beta to generate mature IL-1beta. Neonatal mice with a homozygous deletion of ICE (ICE -/-) are resistant to moderate, but not to severe cerebral hypoxic-ischemic insults, relative to their wild-type controls. We hypothesized that their resistance to moderate hypoxic-ischemic insults is mediated by suppression of the acute inflammatory response to brain injury in the absence of IL-1beta, and that hypoxia-ischemia induced MCP-1 expression would be attenuated in ICE -/- animals. To test this hypothesis, paired litters of 9-10-day-old ICE -/- and wild-type mice underwent right carotid ligation, followed by 40, 70 or 120 min exposure to 10% O2 and ischemia-induced changes in MCP-1 mRNA and protein were compared, using a semi-quantitative reverse-transcription polymerase chain reaction assay and an ELISA, respectively. With a lesioning protocol that elicits minimal injury in wild-types (ligation+40 min 10% O2), there was an attenuation of hypoxia-ischemia-induced MCP-1 production at 8 h post-hypoxia; in contrast, in animals that underwent longer periods of hypoxia-ischemia the magnitude of injury-induced induced MCP-1 production did not differ between wild-type and ICE -/- animals. These results demonstrate both that the acute inflammatory response to hypoxia-ischemia is attenuated in ICE -/- animals, and also that hypoxic-ischemic brain injury stimulates MCP-1 expression even in the absence of IL-1beta activity.

• Authors: H Xu, J D Barks, G P Schielke, F S Silverstein
• Journal: Brain research. Molecular brain research (Brain Res Mol Brain Res) Vol. 90 Issue 1 Pg. 57-67 (May 20 2001) ISSN: 0169-328X [Print] Netherlands
• PMID: 11376856 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chemokine CCL2
• Interleukin-1
• Nerve Tissue Proteins
• Caspase 1

Topics

• Animals
• Animals, Newborn
• Apoptosis
• Asphyxia Neonatorum (metabolism)
• Brain (metabolism, pathology)
• Carotid Arteries
• Caspase 1 (deficiency, genetics, physiology)
• Chemokine CCL2 (biosynthesis, genetics)
• Disease Models, Animal
• Female
• Gene Expression Regulation
• Humans
• Hypoxia-Ischemia, Brain (genetics, metabolism, pathology)
• Infant, Newborn
• Inflammation
• Interleukin-1 (physiology)
• Ligation
• Male
• Mice
• Mice, Knockout
• Nerve Tissue Proteins (biosynthesis, genetics)