title: The type 1 interleukin 1 receptor is not required for the death of murine hippocampal dentate granule cells and microglia activation.
abstract: Alterations in inflammatory process, neuronal death, and glia response have been observed under manipulation of interleukin-1 (IL-1) and subsequent signaling through the type 1 IL-1 receptor (IL-1R1). To investigate the influence of IL-1R1 activation in the pathophysiology of a chemical-induced injury to the murine hippocampus, we examined the level and pattern of neuronal death and neuroinflammation in male weanling mice exposed to trimethyltin hydroxide (2.0 mg TMT/kg, i.p.). Dentate granule cell death occurred at 6 h post-TMT as detected by active caspase 3 immunostaining and presence of lectin positive microglia. The severity of neuronal death and microglia response increased by 12-24 h with elevations in mRNA levels for TNFalpha and IL-1alpha. In IL-1R1 null (IL-1R1-/-) mice, the pattern and severity of neuronal death at 24 or 72 h post-TMT was similar as compared to wildtype (WT) mice. In both groups, mRNA levels for TNFalpha and MIP-1alpha were elevated, no significant change was seen in either IL-1alpha or IL-1beta, and the early activation of microglia, including their ability to progress to a phagocytic phenotype, was maintained. Compared to WT mice, IL-1R1-/- mice displayed a limited glial fibrillary acidic protein (GFAP) astrocytic response, as well as a preferential induction in mRNA levels of Fas signaling components. Cumulatively, these results indicate that IL-1R1 activation is not necessary for TMT-induced death of dentate granule neurons or local activation of microglia; however, IL-1R1 signaling is involved in mediating the structural response of astrocytes to injury and may regulate apoptotic mechanisms via Fas signaling components.
authors.affiliation: Neurotoxicology Group, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA. harry@niehs.nih.gov
authors.forename: G Jean
authors.initials: GJ
authors.lastname: Harry
authors.forename: Jason A
authors.initials: JA
authors.lastname: Funk
authors.forename: Christian
authors.initials: C
authors.lastname: Lefebvre d'Hellencourt
authors.forename: Christopher A
authors.initials: CA
authors.lastname: McPherson
authors.forename: Mineyoshi
authors.initials: M
authors.lastname: Aoyama
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D018891:Dentate Gyrus / Q000166:cytology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011897:Random Allocation; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000502:physiology*; D013997:Time Factors; D014298:Trimethyltin Compounds / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D005904:Glial Fibrillary Acidic Protein; D053582:Interleukin-1alpha; D037102:Lectins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D014298:Trimethyltin Compounds; D014409:Tumor Necrosis Factor-alpha; C037718:trimethyltin hydroxide; D053148:Caspase 3