title: 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.affiliation: Department of Pediatrics, University of Michigan, Rm. 8301 MSRB3, Box 0646, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0646, USA.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.forename: J D
authors.initials: JD
authors.lastname: Barks
authors.forename: G P
authors.initials: GP
authors.lastname: Schielke
authors.forename: F S
authors.initials: FS
authors.lastname: Silverstein
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001238:Asphyxia Neonatorum / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries; D020170:Caspase 1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007231:Infant, Newborn; D007249:Inflammation; D007375:Interleukin-1 / Q000502:physiology; D008026:Ligation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018932:Chemokine CCL2; D007375:Interleukin-1; D009419:Nerve Tissue Proteins; D020170:Caspase 1