Role of cytokines in experimental neurodegenerative and neuroinflammatory disorders
Author: Zhang, Xing-Mei
Date: 2010-09-03
Location: Hörsalen, plan 4, Novum, Huddinge
Time: 9.30
Department: Institutionen för neurobiologi, vårdvetenskap och samhälle / Department of Neurobiology, Care Sciences and Society
View/ Open:
thesis.pdf (453.5Kb)
Abstract
Altered expression of cytokines in response to body injury has diverse actions that can exacerbate, mediate, reduce or inhibit neuronal and myelin damage as well as influence the disease development in a variety of nervous system disorders, such as Alzheimer s disease (AD), multiple sclerosis and Guillain-Barré Syndrome (GBS). In these studies, we attempted to explore the possible roles of tumor necrosis factor (TNF)-α and interleukin (IL)-18 in experimental neurodegenerative and neuroinflammatory disorders.
The role of TNF-α in kainic acid (KA)-induced excitotoxic neurodegeneration has been studied by comparing TNF receptor 1 (TNFR1) knockout (TNFR1-/-) mice with wild-type (WT) mice. After nasal application of KA, TNFR1-/- mice showed significantly severer seizures than WT mice. In addition, obvious neuronal damage, enhanced microglia activation and astrogliosis in hippocampus as well as increased locomotor activity were found in TNFR1-/- mice compared with WT controls. Moreover, CC chemokine receptor 3 expression on activated microglia was increased in TNFR1-/- mice after KA treatment as measured by flow cytometry. These data suggest that TNF-α may play a protective role via TNFR1 signalling in KA-induced neurodegeneration. Epidemiological studies concerning gender differences in AD support the higher prevalence and incidence of AD in women.
The influence of age and gender on excitotoxic neurodegeneration has been investigated by treating C57BL/6 mice (aged females and males as well as adult females and males) with KA. The results showed that aged female mice were more sensitive to KA-induced excitotoxicity associated with severer seizure activity, increased locomotion and rearing in open-field test, prominent hippocampal neuronal damage, enhanced astrocyte proliferation compared with aged males, adult females and adult male mice, respectively. In addition, higher level of brain-derived neurotrophic factor in hippocampi of aged female mice was observed. These results denote that aged female mice are more sensitive to KA-induced excitotoxicity. IL-18 participates in the fundamental inflammatory processes, especially during aging. Based on the above results, we were interested in studying the role of IL-18 in KA-induced neurodegeneration in aged female C57BL/6 mice. We found that aged female IL-18-/- and WT mice showed similar responses to KA insult as demonstrated by comparable seizure activities, behavioral changes and neuronal cell death. However, aged female IL-18-/- mice failed to exhibit as strong microglial activation as WT mice. Interestingly, even though the number of activated microglia was less in KA-treated IL-18-/- mice than in KA-treated WT mice, the proportion of microglia that expressed the cytokines, TNF-α, IL-6 and IL-10 was higher in KA-treated IL-18-/- mice. Deficiency of IL-18 attenuates microglial activation after KA-induced excitotoxicity in aged brain, while the net effects of IL-18 deficiency are balanced by the enhancement of TNF-α, IL-6 and IL-10 production.
To further explore the role of IL-18 in the neurodegeneration and neuroinflammation, another animal model - experimental autoimmune neuritis (EAN) was induced by immunization of mice (IL-18-/-) with P0 protein peptide 180-199. The clinical course was not significantly different between IL-18-/- and WT mice. The splenic mononuclear cell (MNC) proliferation was also similar in both animal groups. However, the percentages of interferon-γ, IL-10 and IL-12 positive cells were decreased among infiltrating MNC of cauda equina in IL-18-/- mice. This indicates that IL-18 deficiency inhibits the production of both Th1 and Th2 cytokines in the target organ of EAN. In summary, TNF-α may play a protective role via TNFR1 signalling in KA-induced neurodegeneration, while IL-18 may not be a key inflammatory cytokine in experimental neurodegenerative and neuroinflammatory disorders.
The role of TNF-α in kainic acid (KA)-induced excitotoxic neurodegeneration has been studied by comparing TNF receptor 1 (TNFR1) knockout (TNFR1-/-) mice with wild-type (WT) mice. After nasal application of KA, TNFR1-/- mice showed significantly severer seizures than WT mice. In addition, obvious neuronal damage, enhanced microglia activation and astrogliosis in hippocampus as well as increased locomotor activity were found in TNFR1-/- mice compared with WT controls. Moreover, CC chemokine receptor 3 expression on activated microglia was increased in TNFR1-/- mice after KA treatment as measured by flow cytometry. These data suggest that TNF-α may play a protective role via TNFR1 signalling in KA-induced neurodegeneration. Epidemiological studies concerning gender differences in AD support the higher prevalence and incidence of AD in women.
The influence of age and gender on excitotoxic neurodegeneration has been investigated by treating C57BL/6 mice (aged females and males as well as adult females and males) with KA. The results showed that aged female mice were more sensitive to KA-induced excitotoxicity associated with severer seizure activity, increased locomotion and rearing in open-field test, prominent hippocampal neuronal damage, enhanced astrocyte proliferation compared with aged males, adult females and adult male mice, respectively. In addition, higher level of brain-derived neurotrophic factor in hippocampi of aged female mice was observed. These results denote that aged female mice are more sensitive to KA-induced excitotoxicity. IL-18 participates in the fundamental inflammatory processes, especially during aging. Based on the above results, we were interested in studying the role of IL-18 in KA-induced neurodegeneration in aged female C57BL/6 mice. We found that aged female IL-18-/- and WT mice showed similar responses to KA insult as demonstrated by comparable seizure activities, behavioral changes and neuronal cell death. However, aged female IL-18-/- mice failed to exhibit as strong microglial activation as WT mice. Interestingly, even though the number of activated microglia was less in KA-treated IL-18-/- mice than in KA-treated WT mice, the proportion of microglia that expressed the cytokines, TNF-α, IL-6 and IL-10 was higher in KA-treated IL-18-/- mice. Deficiency of IL-18 attenuates microglial activation after KA-induced excitotoxicity in aged brain, while the net effects of IL-18 deficiency are balanced by the enhancement of TNF-α, IL-6 and IL-10 production.
To further explore the role of IL-18 in the neurodegeneration and neuroinflammation, another animal model - experimental autoimmune neuritis (EAN) was induced by immunization of mice (IL-18-/-) with P0 protein peptide 180-199. The clinical course was not significantly different between IL-18-/- and WT mice. The splenic mononuclear cell (MNC) proliferation was also similar in both animal groups. However, the percentages of interferon-γ, IL-10 and IL-12 positive cells were decreased among infiltrating MNC of cauda equina in IL-18-/- mice. This indicates that IL-18 deficiency inhibits the production of both Th1 and Th2 cytokines in the target organ of EAN. In summary, TNF-α may play a protective role via TNFR1 signalling in KA-induced neurodegeneration, while IL-18 may not be a key inflammatory cytokine in experimental neurodegenerative and neuroinflammatory disorders.
List of papers:
I. Ming-Ou Lu, Xing-Mei Zhang, Eilhard Mix, Hernan Concha Quezada, Tao Jin, Jie Zhu, and Abdu Adem (2008). "TNF-α receptor 1 deficiency enhances kainic acid-induced hippocampal injury in mice" Journal of Neuroscience Research 86(7): 1608-14.
Pubmed
II. Xing-Mei Zhang, Shun-Wei Zhu, Rui-Sheng Duan, Abdul H. Mohammed, Bengt Winblad, and Jie Zhu (2008). "Gender differences in susceptibility to kainic acid-induced neurodegeneration in aged C57BL/6 mice" NeuroToxicology 29(3): 406-12
Pubmed
III. Xing-Mei Zhang, Tao Jin, Hernan Concha Quezada, Eilhard Mix, Bengt Winblad, and Jie Zhu (1970). "Kainic acid-induced microglial activation is attenuated in aged interleukin-18 deficiency mice" Journal of Neuroinflammation 7: 26
Pubmed
IV. Rui-Sheng Duan, Xing-Mei Zhang, Eilhard Mix, Hernan Concha Quezada, Abdu Adem, and Jie Zhu (2007). "IL-18 deficiency inhibits both Th1 and Th2 cytokine production but not the clinical symptoms in experimental autoimmune neuritis" Journal of Neuroimmunology 183: 162-7
Pubmed
I. Ming-Ou Lu, Xing-Mei Zhang, Eilhard Mix, Hernan Concha Quezada, Tao Jin, Jie Zhu, and Abdu Adem (2008). "TNF-α receptor 1 deficiency enhances kainic acid-induced hippocampal injury in mice" Journal of Neuroscience Research 86(7): 1608-14.
Pubmed
II. Xing-Mei Zhang, Shun-Wei Zhu, Rui-Sheng Duan, Abdul H. Mohammed, Bengt Winblad, and Jie Zhu (2008). "Gender differences in susceptibility to kainic acid-induced neurodegeneration in aged C57BL/6 mice" NeuroToxicology 29(3): 406-12
Pubmed
III. Xing-Mei Zhang, Tao Jin, Hernan Concha Quezada, Eilhard Mix, Bengt Winblad, and Jie Zhu (1970). "Kainic acid-induced microglial activation is attenuated in aged interleukin-18 deficiency mice" Journal of Neuroinflammation 7: 26
Pubmed
IV. Rui-Sheng Duan, Xing-Mei Zhang, Eilhard Mix, Hernan Concha Quezada, Abdu Adem, and Jie Zhu (2007). "IL-18 deficiency inhibits both Th1 and Th2 cytokine production but not the clinical symptoms in experimental autoimmune neuritis" Journal of Neuroimmunology 183: 162-7
Pubmed
Issue date: 2010-08-13
Rights:
Publication year: 2010
ISBN: 978-91-7409-985-0
Statistics
Total Visits
Views | |
---|---|
Role ...(legacy) | 926 |
Role ... | 130 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Role ... | 4 | 0 | 0 | 0 | 1 | 2 | 1 |
File Visits
Views | |
---|---|
thesis.pdf(legacy) | 816 |
thesis.pdf | 299 |
thesis.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 354 |
Germany | 99 |
China | 63 |
Sweden | 49 |
South Korea | 26 |
Denmark | 22 |
Japan | 17 |
France | 15 |
United Kingdom | 14 |
Finland | 8 |
Top cities views
Views | |
---|---|
Sunnyvale | 47 |
Kiez | 35 |
Romeo | 34 |
Seoul | 26 |
Beijing | 24 |
Ballerup | 22 |
Roubaix | 14 |
Stockholm | 13 |
Dublin | 8 |
Ashburn | 7 |