Up-regulation of the inflammatory cytokines IFN-γ and IL-12 and down-regulation of IL-4 in cerebral cortex regions of APPSWE transgenic mice

Abbas, Nagat; Bednar, I.; Mix, Eilhard; Marie, Svedberg; Paterson, David S.; Ljungberg, Anna; Morris, Christopher M.; Winblad, Bengt; Nordberg, Agneta; Zhu, Jie

doi:10.1016/s0165-5728(02)00050-4

Cited by 154 publications

(107 citation statements)

References 36 publications

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“…IL-4 was shown in vitro to suppress microglial production of IFN-␥-induced MHC class II (46), TNF-␣, NO (47), and IL-6 (23), but relatively little is known about its role in microglial function in the CNS, probably because generation of IL-4 in the CNS has not been proved. mRNA for IL-4 was reportedly expressed in human brain (23), and expression levels of mRNA and proteins were markedly decreased in Tg2576 mice, which served as an AD model (48). Decreased hippocampal IL-4 concentration and IL-4-stimulated signaling were also found in aged rats compared with young rats (49).…”

Section: Pathophysiological Significance Of Il-4-induced A␤ Clearancementioning

confidence: 97%

IL-4-Induced Selective Clearance of Oligomeric β-Amyloid Peptide1–42 by Rat Primary Type 2 Microglia

Shimizu

Kawahara

Kajizono

et al. 2008

The Journal of Immunology

131

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A hallmark of immunopathology associated with Alzheimer’s disease is the presence of activated microglia (MG) surrounding senile plaque deposition of β-amyloid (Aβ) peptides. Aβ peptides are believed to be potent activators of MG, which leads to Alzheimer’s disease pathology, but the role of MG subtypes in Aβ clearance still remains unclear. In this study, we found that IL-4 treatment of rat primary-type 2 MG enhanced uptake and degradation of oligomeric Aβ1–42 (o-Aβ1–42). IL-4 treatment induced significant expression of the scavenger receptor CD36 and the Aβ-degrading enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE) but reduced expression of certain other scavenger receptors. Of cytokines and stimulants tested, the anti-inflammatory cytokines IL-4 and IL-13 effectively enhanced CD36, NEP, and IDE. We demonstrated the CD36 contribution to IL-4-induced Aβ clearance: Chinese hamster ovary cells overexpressing CD36 exhibited marked, dose-dependent degradation of 125I-labeled o-Aβ1–42 compared with controls, the degradation being blocked by anti-CD36 Ab. Also, we found IL-4-induced clearance of o-Aβ1–42 in type 2 MG from CD36-expressing WKY/NCrj rats but not in cells from SHR/NCrj rats with dysfunctional CD36 expression. NEP and IDE also contributed to IL-4-induced degradation of Aβ1–42, because their inhibitors, thiorphan and insulin, respectively, significantly suppressed this activity. IL-4-stimulated uptake and degradation of o-Aβ1–42 were selectively enhanced in type 2, but not type 1 MG that express CD40, which suggests that the two MG types may play different neuroimmunomodulating roles in the Aβ-overproducing brain. Thus, selective o-Aβ1–42 clearance, which is induced by IL-4, may provide an additional focus for developing strategies to prevent and treat Alzheimer’s disease.

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Section: Pathophysiological Significance Of Il-4-induced A␤ Clearancementioning

confidence: 97%

IL-4-Induced Selective Clearance of Oligomeric β-Amyloid Peptide1–42 by Rat Primary Type 2 Microglia

Shimizu

Kawahara

Kajizono

et al. 2008

The Journal of Immunology

131

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“…Increased production of interferon-gamma is likely to be the cause of the observed up-regulation of IFITM3 in AD brain. Indeed, overexpression of interferon-gamma has been detected in APP transgenic mice developing amyloid plaques (30). However, we compared AD cases with cognitively normal elderly subjects bearing abundant cerebral Ab deposits, in absence of neurofibrillary pathology.…”

Section: Reproducibility Of Changes In Gene Expression In Ad Brainmentioning

confidence: 99%

Microarray Analysis in Alzheimer's Disease and Normal Aging

et al. 2004

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SummaryThe purpose of this study was to investigate gene expression in Alzheimer's disease (AD), the most common form of senile dementia. We utilized the microarray technology to simultaneously compare the expression profile of 12,000 human genes in cerebral cortex of AD and normal aging. To identify gene expression related to neurodegeneration, beside the presence of amyloid deposition, we used control brains with abundant amyloid plaques, derived from cognitively normal elderly subjects. The microarray analysis indicated that 314 genes were differentially expressed in AD cerebral cortex, with differences greater than 5 folds in 25 genes. RT-PCR performed on a selected group of genes confirmed the increased expression of the interferon-induced protein 3 in AD brain. This protein, which is highly inducible by both type I and type II interferons, was not previously associated with the neurodegenerative disease.

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“…For instance, LPS has been reported to be able to diffuse into the CNS through areas where blood-brain barrier functions are defective, thereby stimulating microglial cells (37). On the other hand IL-4 is detectable in the CNS and its levels are significantly down-regulated in amyloid precursor protein transgenic mice that develop CNS pathology similar to human AD (38). Thus, IL-4 may provide protection against the deleterious effect of proinflammatory stimuli in the CNS.…”

Section: Involvement Of Pi3k-dependent Phosphatase Activity In the Efmentioning

confidence: 99%

IL-4 Down-Regulates Lipopolysaccharide-Induced Formyl Peptide Receptor 2 in Murine Microglial Cells by Inhibiting the Activation of Mitogen-Activated Protein Kinases

Iribarren

Cui

et al. 2003

The Journal of Immunology

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Microglial cells actively participate in proinflammatory responses in the CNS. Upon stimulation with the bacterial LPS, microglial cells express a functional formyl peptide receptor 2 which mediates the chemotactic and activating effects of a variety of polypeptide agonists including amyloid β (Aβ1–42), a critical pathogenic agent in Alzheimer’s disease. In the present study, we found that LPS-induced expression and function of formyl peptide receptor 2 in microglial cells was markedly inhibited by IL-4, a Th2-type cytokine. Our effort to elucidate the mechanistic basis revealed that IL-4 attenuated LPS-stimulated activation of NF-κB, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinase, and the effect of IL-4 was associated with a phosphoinositide 3-kinase pathway-dependent increase in serine/threonine phosphatase activity. These results suggest that IL-4 may play an important role in the maintenance of homeostasis of CNS and in the regulation of the disease process characterized by microglial activation in response to proinflammatory stimulants.

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Up-regulation of the inflammatory cytokines IFN-γ and IL-12 and down-regulation of IL-4 in cerebral cortex regions of APPSWE transgenic mice

Cited by 154 publications

References 36 publications

IL-4-Induced Selective Clearance of Oligomeric β-Amyloid Peptide1–42 by Rat Primary Type 2 Microglia

IL-4-Induced Selective Clearance of Oligomeric β-Amyloid Peptide1–42 by Rat Primary Type 2 Microglia

Microarray Analysis in Alzheimer's Disease and Normal Aging

IL-4 Down-Regulates Lipopolysaccharide-Induced Formyl Peptide Receptor 2 in Murine Microglial Cells by Inhibiting the Activation of Mitogen-Activated Protein Kinases

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