Induction of proinflammatory molecules in mice with amyotrophic lateral sclerosis: no requirement for proapoptotic interleukin-1beta in neurodegeneration.
Recent studies have demonstrated the activation of caspase-1 and caspase-3 in mice expressing mutant superoxide dismutase 1 (SOD1), models of amyotrophic lateral sclerosis. Caspase-1 converts the prointerleukin-1beta into a potent proinflammatory molecule involved in the innate immune response and in neurodegenerative diseases. We report on the chronic expression of interleukin-1beta mRNA in the spinal cord of SOD1G37R mice, together with robust mRNA expression for the nuclear factor-kappaB (NF-kappaB) inhibitor IkappaBalpha, for other proinflammatory cytokines and chemokines (interleukin-6, tumor necrosis factor-alpha, monocyte chemoattractant protein-1) and for the toll-like receptor TLR2 involved in innate immunity. To further assess the interleukin-1beta contribution to neurodegeneration, we generated mice expressing SOD1G37R in a context of interleukin-1beta gene knockout. Surprisingly, the absence of interleukin-1beta had no effect on the life span of SOD1G37R mice, nor on the extent of motor axon degeneration at age 7 and 10 months. Whereas neither compensatory induction of the interleukin-1alpha mRNA nor increases in mRNA levels for IkappaBalpha, tumor necrosis factor-alpha and macrophage chemoattractant protein-1 occurred as a result of interleukin-1beta gene disruption, enhanced levels of TLR2 mRNA were detected in SOD1G37R mice lacking interleukin-1beta. We conclude that interleukin-1beta does not directly contribute to motor neuron degeneration in SOD1G37R mice, but it may act as a modulator of the innate immune response.
Nguyen
M D
MD
Center for Research in Neurosciences, McGill University, The Montreal General Hospital Research Institute, Quebec, Canada.
Julien
J P
JP
Rivest
S
S
D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D029721:Drosophila Proteins; D005786:Gene Expression Regulation; D020672:I-kappa B Proteins; D007113:Immunity, Innate; D007375:Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D015996:Survival Rate; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D008562:Membrane Glycoproteins; C000606205:Nfkbia protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1