Interleukin-1β, interleukin-6, epidermal growth factor and transforming growth factor-α are elevated in the brain from parkinsonian patients

Mogi, Makio; Harada, Minoru; Kondo, T.; Riederer, Peter; Inagaki, Hirofumi; Minami, Masayasu; Nagatsu, Toshiharu

doi:10.1016/0304-3940(94)90508-8

Cited by 779 publications

(497 citation statements)

References 23 publications

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“…The cytokines chosen for assessment were interferon‐γ (IFNγ), tumour necrosis factor‐α (TNFα) and interleukin‐1β (IL‐1β) as these cytokines are linked to both MHC II induction (Dong and Benveniste, 2001) and PD pathogenesis (Mogi et al, 1994a, 1994b; Mount et al, 2007). Saline‐treated MHC II null mice had higher levels of IFNγ than saline‐treated wild‐type mice ( P = 0.040 ANOVA, Student Newman Keuls post hoc test; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, some of these pro‐inflammatory cytokines, especially IFNγ, may be derived from infiltrating CD4 + T‐cells. Irrespective of their source, all these cytokines are increased in PD patients (Mogi et al, 1994a, 1994b; Mount et al, 2007) and are documented to have negative impacts on MPTP toxicity (Mount et al, 2007; Ferger et al, 2004). Indeed IFNγ null mice showed significant attenuation of MPTP‐induced loss of dopaminergic neurons together with ablation of microgliosis (Mount et al, 2007), suggesting that IFNγ activation of microglia is important in MPTP toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…The pathogenesis of this debilitating disease is poorly understood (Dauer and Przedborski, 2004), but inflammatory processes have been implicated in the degeneration of the dopaminergic neurons. This is supported by the activated glial cells and the upregulation of pro‐inflammatory cytokines seen in both models of PD and PD patients (Czlonkowska et al, 1996; Hebert et al, 2003; McGeer et al, 1988; Mogi et al, 1994a,b).…”

Section: Introductionmentioning

confidence: 94%

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Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Martin

Santoro

Mustafa

et al. 2015

Glia

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Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post‐mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). In wild‐type mice MHC II levels in the ventral midbrain were upregulated 1–2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP‐induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon‐γ or tumour necrosis factor‐α in the brain after MPTP treatment, as was found in wild‐type mice. However, interleukin‐1β was significantly increased in both wild‐type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II‐mediated T cell activation is required for the full expression of pathology in this model of PD. GLIA 2016;64:386–395

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

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Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Martin

Santoro

Mustafa

et al. 2015

Glia

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“…Neuroinflammation observed in PD is attributed to activated microglia, which are abundant in the post-mortem brains of PD patients [116,117]. Postmortem CSF and brain tissue from PD patients have elevated TNF and IFN- levels [118,119]. Rodent models of chronic LPS infusion lead to brain inflammation with subsequent delay and selective degeneration of dopaminergic neurons [120].…”

Section: Proteotoxic Stress In the Pathogenesis Of Diseases Not Formementioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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“…Moreover, the SN is particularly vulnerable to microglial inflammation, as induced by lipopolysaccharide (LPS) injections (205,206). Extensive microgliosis, pro-inflammatory cytokines and oxidative stress-mediated damage is found in post mortem brains of PD patients (120-123, 196, 207, 208) as well as in animal models of PD (124,190,208,209), including upregulated expression of major histocompatibility complex (MHC) molecules and pro-inflammatory cytokines, including TNF-α and IL-1β (120,(122)(123)(124)190) and reactive oxygen-and nitrogen species (190,196,208). These features were co-localized with microglia and were increased in areas most affected by dopaminergic cell death, suggesting a significant role of microglia and inflammation in the degenerative process (153).…”

Section: Microgliamentioning

confidence: 99%

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

et al. 2011

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Interleukin-1β, interleukin-6, epidermal growth factor and transforming growth factor-α are elevated in the brain from parkinsonian patients

Cited by 779 publications

References 23 publications

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

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