The type 1 interleukin 1 receptor is not required for the death of murine hippocampal dentate granule cells and microglia activation.
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.
Harry
G Jean
GJ
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
Funk
Jason A
JA
Lefebvre d'Hellencourt
Christian
C
McPherson
Christopher A
CA
Aoyama
Mineyoshi
M
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
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