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IL-17A is increased in the serum and in spinal cord CD8 and mast cells of ALS patients.

Fiala M, Chattopadhay M, La Cava A, Tse E, Liu G, Lourenco E, Eskin A, Liu PT, Magpantay L, Tse S, Mahanian M, Weitzman R, Tong J, Nguyen C, Cho T, Koo P, Sayre J, Martinez-Maza O, Rosenthal MJ, Wiedau-Pazos M - J Neuroinflammation (2010)

Bottom Line: In a microarray analysis of 28,869 genes, stimulation of peripheral blood mononuclear cells by mutant superoxide dismutase-1 induced four-fold higher transcripts of interleukin-1α (IL-1α), IL-6, CCL20, matrix metallopeptidase 1, and tissue factor pathway inhibitor 2 in mononuclear cells of patients as compared to controls, whereas the anti-inflammatory cytokine interleukin-10 (IL-10) was increased in mononuclear cells of control subjects.Aggregated wild type SOD-1 in sALS neurons could induce in mononuclear cells the cytokines inducing chronic inflammation in sALS spinal cord, in particular IL-6 and IL-17A, damaging neurons.Immune modulation of chronic inflammation may be a new approach to sALS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System, 650 Charles E, Young Dr, South, Los Angeles, CA 90095-1735, USA. Fiala@mednet.ucla.edu

ABSTRACT
The contribution of inflammation to neurodegenerative diseases is increasingly recognized, but the role of inflammation in sporadic amyotrophic lateral sclerosis (sALS) is not well understood and no animal model is available. We used enzyme-linked immunosorbent assays (ELISAs) to measure the cytokine interleukin-17A (IL-17A) in the serum of ALS patients (n = 32; 28 sporadic ALS (sALS) and 4 familial ALS (fALS)) and control subjects (n = 14; 10 healthy subjects and 4 with autoimmune disorders). IL-17A serum concentrations were 5767 ± 2700 pg/ml (mean ± SEM) in sALS patients and 937 ± 927 pg/ml in fALS patients in comparison to 7 ± 2 pg/ml in control subjects without autoimmune disorders (p = 0.008 ALS patients vs. control subjects by Mann-Whitney test). Sixty-four percent of patients and no control subjects had IL-17A serum concentrations > 50 pg/ml (p = 0.003 ALS patients vs. healthy subjects by Fisher's exact test). The spinal cords of sALS (n = 8), but not control subjects (n = 4), were infiltrated by interleukin-1β- (IL-1β-), and tumor necrosis factor-α-positive macrophages (co-localizing with neurons), IL-17A-positive CD8 cells, and IL-17A-positive mast cells. Mononuclear cells treated with aggregated forms of wild type superoxide dismutase-1 (SOD-1) showed induction of the cytokines IL-1β, interleukin-6 (IL-6), and interleukin-23 (IL-23) that may be responsible for induction of IL-17A. In a microarray analysis of 28,869 genes, stimulation of peripheral blood mononuclear cells by mutant superoxide dismutase-1 induced four-fold higher transcripts of interleukin-1α (IL-1α), IL-6, CCL20, matrix metallopeptidase 1, and tissue factor pathway inhibitor 2 in mononuclear cells of patients as compared to controls, whereas the anti-inflammatory cytokine interleukin-10 (IL-10) was increased in mononuclear cells of control subjects. Aggregated wild type SOD-1 in sALS neurons could induce in mononuclear cells the cytokines inducing chronic inflammation in sALS spinal cord, in particular IL-6 and IL-17A, damaging neurons. Immune modulation of chronic inflammation may be a new approach to sALS.

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Transcriptional upregulation by G37R SOD-1 of cytokines, chemokines, MMP1 and TFPI2. The values after Robust Multi-array Analysis (RMA) are displayed for patients and control subjects and the ratio of values (patient/control) for each gene is shown. Note the cytokines (*) increased and those (**) decreased in patients in comparison to controls.
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Figure 8: Transcriptional upregulation by G37R SOD-1 of cytokines, chemokines, MMP1 and TFPI2. The values after Robust Multi-array Analysis (RMA) are displayed for patients and control subjects and the ratio of values (patient/control) for each gene is shown. Note the cytokines (*) increased and those (**) decreased in patients in comparison to controls.

Mentions: The responses to mutant SOD-1 were analyzed at the transcriptional level by microarray hybridization. The analysis of 28,869 transcript cluster identifications in peripheral blood mononuclear cells of 2 controls and 3 patients (stimulated 18 hr by mutant SOD-1) showed strong stimulation of 7 cytokines (IL-10, IL-23A, granulocyte macrophage colony stimulating factor, IL-1β, IL-1α, IL-6 and IL-7) in both patients and control subjects (Figure 8). Of these, the increase in transcription of IL-1α and IL-6 was ~ four-fold higher in patients compared to controls. In agreement with the constitutive production of IL-17A, its mRNA was not stimulated by G37R SOD-1. The chemokines CCL2, CXCL1, CXCL2, and CXCL3 were transcribed at a high level in patients as well as controls at baseline and after stimulation. G37R SOD-1 stimulated more CCL20 (5.5 fold), matrix metallopeptidase 1 (4.5fold), and tissue factor pathway inhibitor 2 (11.7 fold) in PBMC's of patients, as compared to control subjects. On the other hand, the anti-inflammatory cytokine IL-10 mRNA was stimulated more (2.0 fold) in PBMC's of control subjects, as compared to patients.


IL-17A is increased in the serum and in spinal cord CD8 and mast cells of ALS patients.

Fiala M, Chattopadhay M, La Cava A, Tse E, Liu G, Lourenco E, Eskin A, Liu PT, Magpantay L, Tse S, Mahanian M, Weitzman R, Tong J, Nguyen C, Cho T, Koo P, Sayre J, Martinez-Maza O, Rosenthal MJ, Wiedau-Pazos M - J Neuroinflammation (2010)

Transcriptional upregulation by G37R SOD-1 of cytokines, chemokines, MMP1 and TFPI2. The values after Robust Multi-array Analysis (RMA) are displayed for patients and control subjects and the ratio of values (patient/control) for each gene is shown. Note the cytokines (*) increased and those (**) decreased in patients in comparison to controls.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992053&req=5

Figure 8: Transcriptional upregulation by G37R SOD-1 of cytokines, chemokines, MMP1 and TFPI2. The values after Robust Multi-array Analysis (RMA) are displayed for patients and control subjects and the ratio of values (patient/control) for each gene is shown. Note the cytokines (*) increased and those (**) decreased in patients in comparison to controls.
Mentions: The responses to mutant SOD-1 were analyzed at the transcriptional level by microarray hybridization. The analysis of 28,869 transcript cluster identifications in peripheral blood mononuclear cells of 2 controls and 3 patients (stimulated 18 hr by mutant SOD-1) showed strong stimulation of 7 cytokines (IL-10, IL-23A, granulocyte macrophage colony stimulating factor, IL-1β, IL-1α, IL-6 and IL-7) in both patients and control subjects (Figure 8). Of these, the increase in transcription of IL-1α and IL-6 was ~ four-fold higher in patients compared to controls. In agreement with the constitutive production of IL-17A, its mRNA was not stimulated by G37R SOD-1. The chemokines CCL2, CXCL1, CXCL2, and CXCL3 were transcribed at a high level in patients as well as controls at baseline and after stimulation. G37R SOD-1 stimulated more CCL20 (5.5 fold), matrix metallopeptidase 1 (4.5fold), and tissue factor pathway inhibitor 2 (11.7 fold) in PBMC's of patients, as compared to control subjects. On the other hand, the anti-inflammatory cytokine IL-10 mRNA was stimulated more (2.0 fold) in PBMC's of control subjects, as compared to patients.

Bottom Line: In a microarray analysis of 28,869 genes, stimulation of peripheral blood mononuclear cells by mutant superoxide dismutase-1 induced four-fold higher transcripts of interleukin-1α (IL-1α), IL-6, CCL20, matrix metallopeptidase 1, and tissue factor pathway inhibitor 2 in mononuclear cells of patients as compared to controls, whereas the anti-inflammatory cytokine interleukin-10 (IL-10) was increased in mononuclear cells of control subjects.Aggregated wild type SOD-1 in sALS neurons could induce in mononuclear cells the cytokines inducing chronic inflammation in sALS spinal cord, in particular IL-6 and IL-17A, damaging neurons.Immune modulation of chronic inflammation may be a new approach to sALS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System, 650 Charles E, Young Dr, South, Los Angeles, CA 90095-1735, USA. Fiala@mednet.ucla.edu

ABSTRACT
The contribution of inflammation to neurodegenerative diseases is increasingly recognized, but the role of inflammation in sporadic amyotrophic lateral sclerosis (sALS) is not well understood and no animal model is available. We used enzyme-linked immunosorbent assays (ELISAs) to measure the cytokine interleukin-17A (IL-17A) in the serum of ALS patients (n = 32; 28 sporadic ALS (sALS) and 4 familial ALS (fALS)) and control subjects (n = 14; 10 healthy subjects and 4 with autoimmune disorders). IL-17A serum concentrations were 5767 ± 2700 pg/ml (mean ± SEM) in sALS patients and 937 ± 927 pg/ml in fALS patients in comparison to 7 ± 2 pg/ml in control subjects without autoimmune disorders (p = 0.008 ALS patients vs. control subjects by Mann-Whitney test). Sixty-four percent of patients and no control subjects had IL-17A serum concentrations > 50 pg/ml (p = 0.003 ALS patients vs. healthy subjects by Fisher's exact test). The spinal cords of sALS (n = 8), but not control subjects (n = 4), were infiltrated by interleukin-1β- (IL-1β-), and tumor necrosis factor-α-positive macrophages (co-localizing with neurons), IL-17A-positive CD8 cells, and IL-17A-positive mast cells. Mononuclear cells treated with aggregated forms of wild type superoxide dismutase-1 (SOD-1) showed induction of the cytokines IL-1β, interleukin-6 (IL-6), and interleukin-23 (IL-23) that may be responsible for induction of IL-17A. In a microarray analysis of 28,869 genes, stimulation of peripheral blood mononuclear cells by mutant superoxide dismutase-1 induced four-fold higher transcripts of interleukin-1α (IL-1α), IL-6, CCL20, matrix metallopeptidase 1, and tissue factor pathway inhibitor 2 in mononuclear cells of patients as compared to controls, whereas the anti-inflammatory cytokine interleukin-10 (IL-10) was increased in mononuclear cells of control subjects. Aggregated wild type SOD-1 in sALS neurons could induce in mononuclear cells the cytokines inducing chronic inflammation in sALS spinal cord, in particular IL-6 and IL-17A, damaging neurons. Immune modulation of chronic inflammation may be a new approach to sALS.

Show MeSH
Related in: MedlinePlus