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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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Fibrillar and APO wild-type SOD-1, and APO and AI mutant forms of SOD-1 induce IL-1β and IL-6. Peripheral blood mononuclear cells of two sALS patients were stimulated by the indicated SOD-1 proteins and cytokines were measured in the supernatant after 18 h. Note positive dose-response of IL-1β and IL-6 to fibrillar and APO wild-type SOD-1(A, D), and to APO and AI forms of G37R and D101N SOD-1 (B, C, E, F) (open symbols = patient 1; closed symbols = patient 2)
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Figure 6: Fibrillar and APO wild-type SOD-1, and APO and AI mutant forms of SOD-1 induce IL-1β and IL-6. Peripheral blood mononuclear cells of two sALS patients were stimulated by the indicated SOD-1 proteins and cytokines were measured in the supernatant after 18 h. Note positive dose-response of IL-1β and IL-6 to fibrillar and APO wild-type SOD-1(A, D), and to APO and AI forms of G37R and D101N SOD-1 (B, C, E, F) (open symbols = patient 1; closed symbols = patient 2)

Mentions: To clarify whether certain physical forms of SOD-1 could induce the cytokines IL-1β, IL-6 and IL-23, which can polarize T cells into the TH17 subset, we tested their induction by three forms of wild type and mutant SOD-1: as-isolated (AI), demetallated (APO), and fibrillar (Figure 6). These preparations had no significant levels of endotoxin (see Methods). IL-1β and IL-6 are the central pro-inflammatory cytokines and their induction by different physical forms of SOD-1 identifies these forms as responsible for inflammation. The dose-response experiment with PBMC's of two ALS patients and the wild type SOD-1 proteins showed induction by the fibrillar and APo forms, but not the AI form; and the experiment with the G37R and D101N SOD-1 mutant SOD-1 proteins, showed induction by the AI and APO forms, but not the fibrillar form.


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)

Fibrillar and APO wild-type SOD-1, and APO and AI mutant forms of SOD-1 induce IL-1β and IL-6. Peripheral blood mononuclear cells of two sALS patients were stimulated by the indicated SOD-1 proteins and cytokines were measured in the supernatant after 18 h. Note positive dose-response of IL-1β and IL-6 to fibrillar and APO wild-type SOD-1(A, D), and to APO and AI forms of G37R and D101N SOD-1 (B, C, E, F) (open symbols = patient 1; closed symbols = patient 2)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Fibrillar and APO wild-type SOD-1, and APO and AI mutant forms of SOD-1 induce IL-1β and IL-6. Peripheral blood mononuclear cells of two sALS patients were stimulated by the indicated SOD-1 proteins and cytokines were measured in the supernatant after 18 h. Note positive dose-response of IL-1β and IL-6 to fibrillar and APO wild-type SOD-1(A, D), and to APO and AI forms of G37R and D101N SOD-1 (B, C, E, F) (open symbols = patient 1; closed symbols = patient 2)
Mentions: To clarify whether certain physical forms of SOD-1 could induce the cytokines IL-1β, IL-6 and IL-23, which can polarize T cells into the TH17 subset, we tested their induction by three forms of wild type and mutant SOD-1: as-isolated (AI), demetallated (APO), and fibrillar (Figure 6). These preparations had no significant levels of endotoxin (see Methods). IL-1β and IL-6 are the central pro-inflammatory cytokines and their induction by different physical forms of SOD-1 identifies these forms as responsible for inflammation. The dose-response experiment with PBMC's of two ALS patients and the wild type SOD-1 proteins showed induction by the fibrillar and APo forms, but not the AI form; and the experiment with the G37R and D101N SOD-1 mutant SOD-1 proteins, showed induction by the AI and APO forms, but not the fibrillar form.

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