Interleukin-6 Deficiency Does Not Affect Motor Neuron Disease Caused by Superoxide Dismutase 1 Mutation.

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, progressive, motor neuron degenerative disease. Recent evidence indicates that inflammation is associated with many neurodegenerative diseases including ALS. Previously, abnormal levels of inflammatory cytokines including IL-1β, IL-6 and TNF-α were described in ALS patients and/or in mouse ALS models. In addition, one study showed that blocking IL-1β could slow down progression of ALS-like symptoms in mice. In this study, we examined a role for IL-6 in ALS, using an animal model for familial ALS.Mice with mutant SOD1 (G93A) transgene, a model for familial ALS, were used in this study. The expression of the major inflammatory cytokines, IL-6, IL-1β and TNF-α, in spinal cords of these SOD1 transgenic (TG) mice were assessed by real time PCR. Mice were then crossed with IL-6(-/-) mice to generate SOD1TG/IL-6(-/-) mice. SOD1 TG/IL-6(-/-) mice (n = 17) were compared with SOD1 TG/IL-6(+/-) mice (n = 18), SOD1 TG/IL-6(+/+) mice (n = 11), WT mice (n = 15), IL-6(+/-) mice (n = 5) and IL-6(-/-) mice (n = 8), with respect to neurological disease severity score, body weight and the survival. We also histologically compared the motor neuron loss in lumber spinal cords and the atrophy of hamstring muscles between these mouse groups.Levels of IL-6, IL-1β and TNF-α in spinal cords of SOD1 TG mice was increased compared to WT mice. However, SOD1 TG/IL-6(-/-) mice exhibited weight loss, deterioration in motor function and shortened lifespan (167.55 ± 11.52 days), similarly to SOD1 TG /IL-6(+/+) mice (164.31±12.16 days). Motor neuron numbers and IL-1β and TNF-α levels in spinal cords were not significantly different in SOD1 TG /IL-6(-/-) mice and SOD1 TG /IL-6 (+/+) mice.These results provide compelling preclinical evidence indicating that IL-6 does not directly contribute to motor neuron disease caused by SOD1 mutations

Correlation of increased serum leucine-rich α2-glycoprotein levels with disease prognosis, progression, and activity of interstitial pneumonia in patients with dermatomyositis: A retrospective study.

OBJECTIVE:To investigate whether leucine-rich α2-glycoprotein (LRG) can be a biomarker for the disease activity, progression, and prognosis of interstitial pneumonia (IP) in patients with dermatomyositis (DM). METHODS:Correlations between the clinical findings and serum LRG levels were investigated in 46 patients with DM-IP (33 with acute/subacute IP [A/SIP] and 13 patients with chronic IP [CIP], including 10 fatal cases of IP). RESULTS:The median serum LRG level of 18.4 (14.6-25.2) μg/mL in DM-IP patients was higher than that in healthy control subjects. The median levels of serum LRG at baseline and at 2 and 4 weeks after the initiation of treatment in the patients who died were significantly higher than those in the surviving patients (P = 0.026, 0.029, and 0.008, respectively). The median level of serum LRG in the DM-A/SIP patients was significantly higher than that in the DM-CIP patients (P = 0.0004), and that in the anti-MDA5-Ab-positive group was slightly higher than that in the anti-ARS-Ab-positive group. The serum LRG levels correlated significantly with the serum levels of LDH, C-reactive protein, ferritin, AaDO2, %DLco, and total ground-glass opacity score. The survival rate after 24 weeks in patients with an initial LRG level ≥ 17.6 μg/mL (survival rate: 40%) was significantly lower than that in patients with an initial LRG level < 17.6 μg/mL (100%) (P = 0.0009). CONCLUSION:The serum LRG level may be a promising marker of disease activity, progression, and prognosis in patients with DM-IP

Karyopherin alpha2 is essential for rRNA transcription and protein synthesis in proliferative keratinocytes.

Karyopherin proteins mediate nucleocytoplasmic trafficking and are critical for protein and RNA subcellular localization. Recent studies suggest KPNA2 expression is induced in tumor cells and is strongly associated with prognosis, although the precise roles and mechanisms of KPNA2 overexpression in proliferative disorders have not been defined. We found that KPNA2 expression is induced in various proliferative disorders of the skin such as psoriasis, Bowen's disease, actinic keratosis, squamous cell carcinoma, Paget's disease, Merkel cell carcinoma, and mycosis fungoides. siRNA-mediated KPNA suppression revealed that KPNA2 is essential for significant suppression of HaCaT proliferation under starvation conditions. Ribosomal RNA transcription and protein synthesis were suppressed by starvation combined with knockdown of KPNA (including KPNA2) expression. KPNA2 localized to the nucleolus and interacted with proteins associated with mRNA processing, ribonucleoprotein complex biogenesis, chromatin modification, and transcription, as demonstrated by tandem affinity purification and mass spectrometry. KPNA2 may be an important promoter of ribosomal RNA and protein synthesis in tumor cells

Relative changes in body weight, clinical score and survival in ALS mice.

<p><b>(A-F)</b> Hind limb extension of WT mouse, IL-6(-/-) mouse (160–180 days of age), SOD1 TG/IL-6(+/+) mice and SOD1 TG/IL-6(-/-) mice (the early stage and the end stage), when suspended by their tail. <b>(G)</b> Kaplan-Meier time–to-failure plot for onset of symptomatic neurological disease in ALS mice. Neurological symptoms of SOD1 TG/IL-6(-/-) (n = 17), SOD1 TG/IL-6(+/-) (n = 18) and SOD1 TG/IL-6(+/+) (n = 11) were monitored. The age at which mice attain a neurological severity score 2 is taken to be definitive onset of symptomatic neurological disease (p = 0.597 by log rank test for onset of symptomatic neurological disease). <b>(H)</b> The clinical score of SOD1 TG/IL-6(-/-) mice in comparison with those of SOD1 TG/IL-6(+/-) mice and SOD1 TG/IL-6(+/+) mice. Score criteria (severity from 0 to 4) are shown in materials and methods. SOD1 TG/IL-6 (-/-) (n = 17), SOD1 TG/IL-6(+/-) (n = 18), SOD1 TG /IL-6(+/+) (n = 11), IL-6(-/-) (n = 8), WT (n = 15), IL-6(+/-) (n = 5). WT, IL-6(-/-) or IL-6(+/-) mice showed no disease symptoms. <b>(I)</b> Relative changes in body weight of SOD1 TG/IL-6(-/-) mice (n = 17), SOD1 TG /IL-6(+/-) mice (n = 18) and SOD1 TG /IL-6(+/+) mice (n = 11). Peak body weight of each mouse was calculated as 1. (<b>J</b>) Kaplan-Meier time–to-failure plot for onset of body weight loss of SOD1 TG/IL-6(-/-), SOD1 TG/IL-6(+/-) and SOD1 TG/IL-6(+/+) mice. The age at which mice attained a peak body weight was analyzed (p = 0.595 by log rank test). (<b>K</b>) Kaplan-Meier time–to-failure plot for survival of SOD1 TG/IL-6(-/-), SOD1 TG/IL-6(+/-) and SOD1 TG/IL-6(+/+) mice (p = 0.430 by log rank test). The survival of SOD1 TG/IL-6(-/-) (n = 17), SOD1 TG/IL-6(+/-) (n = 18) and SOD1 TG/IL-6(+/+) (n = 11) was monitored. The mean (± SD) life spans were; SOD1 TG/IL-6(-/-) 167.55 ± 11.52 days, SOD1 TG/IL-6(+/-) 161.82 ± 12.69 days, TG/IL-6(+/+) 164.31 ± 12.16 days.</p

Histological analysis of motor neuron loss and muscle atrophy in ALS mice.

<p>(A, B, C, D, E) HE staining of hamstring muscles from the early stage and the end stage of ALS mice and control mice with indicated genotype. Scale bars: 50 μm. (F, G, H, I, J) Lumber spinal cords from mice with indicated genotypes at the early and the end stage were stained with Cresyl violet solution (Nissl staining). Scale bars: 50μm. (K) A representative image of Nissl-stained mouse spinal cord. Boxed area is a region defined as the anterior horn for motor neuron counting. (L) Quantitative cell counts of motor neurons in the anterior horn section. Spinal cord sections from mice with indicated genotype at the early and the end stage were stained with Cresyl violet solution and motor neurons were counted (*p<0.05 and **p<0.01 by Tukey Kramer post-hoc test).</p