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Type I Vs. Type II Cytokine Levels as a Function of SOD1 G93A Mouse Amyotrophic Lateral Sclerosis Disease Progression.

Jeyachandran A, Mertens B, McKissick EA, Mitchell CS - Front Cell Neurosci (2015)

Bottom Line: A significant increase in TG cytokine levels was found when compared to WT cytokine levels across the entire SOD1 G93A lifespan for majority of the cytokines.The rates of change of the individual cytokines, and type I and type II were not significantly different; however, the mean fold change of type I was expressed at significantly higher levels than type II levels across all stages with the difference between the means becoming more pronounced at the end stage.Very early immunoregulatory treatment is necessary to successfully interrupt ALS-induced neuroinflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Georgia Institute of Technology and Emory University Atlanta, GA, USA.

ABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is a fatal motoneuron disease that is characterized by the degradation of neurons throughout the central nervous system. Inflammation have been cited a key contributor to ALS neurodegeneration, but the timeline of cytokine upregulation remains unresolved. The goal of this study was to temporally examine the correlation between the varying levels of pro-inflammatory type I cytokines (IL-1β, IL-1α, IL-12, TNF-α, and GFAP) and anti-inflammatory type II cytokines (IL-4, IL-6, IL-10) throughout the progression of ALS in the SOD1 G93A mouse model. Cytokine level data from high copy SOD1 G93A transgenic mice was collected from 66 peer-reviewed studies. For each corresponding experimental time point, the ratio of transgenic to wild type (TG/WT) cytokine was calculated. One-way ANOVA and t-tests with Bonferonni correction were used to analyze the data. Meta-analysis was performed for four discrete stages: early, pre-onset, post-onset, and end stage. A significant increase in TG cytokine levels was found when compared to WT cytokine levels across the entire SOD1 G93A lifespan for majority of the cytokines. The rates of change of the individual cytokines, and type I and type II were not significantly different; however, the mean fold change of type I was expressed at significantly higher levels than type II levels across all stages with the difference between the means becoming more pronounced at the end stage. An overexpression of cytokines occurred both before and after the onset of ALS symptoms. The trend between pro-inflammatory type I and type II cytokine mean levels indicate a progressive instability of the dynamic balance between pro- and anti-inflammatory cytokines as anti-inflammatory cytokines fail to mediate the pronounced increase in pro-inflammatory cytokines. Very early immunoregulatory treatment is necessary to successfully interrupt ALS-induced neuroinflammation.

No MeSH data available.


Related in: MedlinePlus

Means of normalized type I and type II for each of the four SOD1 G93A ALS mouse disease stages: early, pre-onset, post-onset, and end stage. Type I cytokines were significantly higher than type II cytokines for each of the four stages. Statistically significant differences between SOD1 G93A transgenic mice (TG) and wild type (WT) levels within a disease stage are marked with asterisk (*). Statistically significant positive or negative fold changes across consecutive stages are represented by plus (+) or minus (–), respectfully. Significance was adjusted to p < 0.006 using Bonferroni correction. Error bars represent confidence intervals.
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Figure 4: Means of normalized type I and type II for each of the four SOD1 G93A ALS mouse disease stages: early, pre-onset, post-onset, and end stage. Type I cytokines were significantly higher than type II cytokines for each of the four stages. Statistically significant differences between SOD1 G93A transgenic mice (TG) and wild type (WT) levels within a disease stage are marked with asterisk (*). Statistically significant positive or negative fold changes across consecutive stages are represented by plus (+) or minus (–), respectfully. Significance was adjusted to p < 0.006 using Bonferroni correction. Error bars represent confidence intervals.

Mentions: Among the individual type I cytokines, IL-1α, IL-1ß, and GFAP show significance in their fold increase (p < 0.0001) across all of the four stages. TNF-α shows significance in fold increase in all stages except for pre-onset, and IL-12 does not show any significance at stages where sufficient data was present to be tested. Across aggregated type I cytokines, increase of TG levels relative to WT levels is statistically significant for each disease stage (Figure 4).


Type I Vs. Type II Cytokine Levels as a Function of SOD1 G93A Mouse Amyotrophic Lateral Sclerosis Disease Progression.

Jeyachandran A, Mertens B, McKissick EA, Mitchell CS - Front Cell Neurosci (2015)

Means of normalized type I and type II for each of the four SOD1 G93A ALS mouse disease stages: early, pre-onset, post-onset, and end stage. Type I cytokines were significantly higher than type II cytokines for each of the four stages. Statistically significant differences between SOD1 G93A transgenic mice (TG) and wild type (WT) levels within a disease stage are marked with asterisk (*). Statistically significant positive or negative fold changes across consecutive stages are represented by plus (+) or minus (–), respectfully. Significance was adjusted to p < 0.006 using Bonferroni correction. Error bars represent confidence intervals.
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Figure 4: Means of normalized type I and type II for each of the four SOD1 G93A ALS mouse disease stages: early, pre-onset, post-onset, and end stage. Type I cytokines were significantly higher than type II cytokines for each of the four stages. Statistically significant differences between SOD1 G93A transgenic mice (TG) and wild type (WT) levels within a disease stage are marked with asterisk (*). Statistically significant positive or negative fold changes across consecutive stages are represented by plus (+) or minus (–), respectfully. Significance was adjusted to p < 0.006 using Bonferroni correction. Error bars represent confidence intervals.
Mentions: Among the individual type I cytokines, IL-1α, IL-1ß, and GFAP show significance in their fold increase (p < 0.0001) across all of the four stages. TNF-α shows significance in fold increase in all stages except for pre-onset, and IL-12 does not show any significance at stages where sufficient data was present to be tested. Across aggregated type I cytokines, increase of TG levels relative to WT levels is statistically significant for each disease stage (Figure 4).

Bottom Line: A significant increase in TG cytokine levels was found when compared to WT cytokine levels across the entire SOD1 G93A lifespan for majority of the cytokines.The rates of change of the individual cytokines, and type I and type II were not significantly different; however, the mean fold change of type I was expressed at significantly higher levels than type II levels across all stages with the difference between the means becoming more pronounced at the end stage.Very early immunoregulatory treatment is necessary to successfully interrupt ALS-induced neuroinflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Georgia Institute of Technology and Emory University Atlanta, GA, USA.

ABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is a fatal motoneuron disease that is characterized by the degradation of neurons throughout the central nervous system. Inflammation have been cited a key contributor to ALS neurodegeneration, but the timeline of cytokine upregulation remains unresolved. The goal of this study was to temporally examine the correlation between the varying levels of pro-inflammatory type I cytokines (IL-1β, IL-1α, IL-12, TNF-α, and GFAP) and anti-inflammatory type II cytokines (IL-4, IL-6, IL-10) throughout the progression of ALS in the SOD1 G93A mouse model. Cytokine level data from high copy SOD1 G93A transgenic mice was collected from 66 peer-reviewed studies. For each corresponding experimental time point, the ratio of transgenic to wild type (TG/WT) cytokine was calculated. One-way ANOVA and t-tests with Bonferonni correction were used to analyze the data. Meta-analysis was performed for four discrete stages: early, pre-onset, post-onset, and end stage. A significant increase in TG cytokine levels was found when compared to WT cytokine levels across the entire SOD1 G93A lifespan for majority of the cytokines. The rates of change of the individual cytokines, and type I and type II were not significantly different; however, the mean fold change of type I was expressed at significantly higher levels than type II levels across all stages with the difference between the means becoming more pronounced at the end stage. An overexpression of cytokines occurred both before and after the onset of ALS symptoms. The trend between pro-inflammatory type I and type II cytokine mean levels indicate a progressive instability of the dynamic balance between pro- and anti-inflammatory cytokines as anti-inflammatory cytokines fail to mediate the pronounced increase in pro-inflammatory cytokines. Very early immunoregulatory treatment is necessary to successfully interrupt ALS-induced neuroinflammation.

No MeSH data available.


Related in: MedlinePlus