High-dose intravenous immunoglobulin therapy for rapidly progressive interstitial pneumonitis accompanied by anti-melanoma differentiation-associated gene 5 antibody-positive amyopathic dermatomyositis.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive amyopathic dermatomyositis (ADM) associated with rapidly progressive interstitial pneumonitis (RPIP) frequently has a poor prognosis and optimal treatment is not well defined. Here, we report a 62-year-old Japanese man with anti-MDA5 antibody-positive ADM associated with RPIP presented with progressive shortness of breath, Heliotrope rash, Gottron's papules, arthralgia, and fatigue but no sign of muscle weakness. Laboratory investigation revealed serum levels of the following biomarkers: ferritin, 1393 ng/mL; Krebs von der Lungen-6, 1880 U/mL; and creatine kinase, 85 U/L. Computed tomography (CT) images showed diffuse ground-glass opacity in both lung fields. Because anti-MDA5 was positive, we made a diagnosis of ADM associated with RPIP and initiated treatment. Following five courses of combination therapy with prednisolone, cyclosporine A, and intravenous cyclophosphamide (IVCY), IVCY treatment was switched to high-dose intravenous immunoglobulin therapy (IVIg) because of the reactivation of interstitial pneumonia with an increased serum ferritin level. Additional treatment with IVIg improved RPIP, with normalization of anti-ADM antibody levels. Therefore, IVIg mayt be a new candidate treatment for anti-MDA5 antibody-positive ADM associated with RPIP.

Liver X receptor α is involved in the transcriptional regulation of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene.

The activity of 6-phosphofructo-1-kinase is strictly controlled by fructose-2,6-bisphosphate, the level of which is regulated by another enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2/FBP2). PFK2/FBP2 is a bifunctional enzyme, having kinase and phosphatase activities, and regulates both glycolysis and gluconeogenesis. Here, we examined the hormonal regulation of the PFK2/FBP2 gene in vitro using the reporter assay, the electromobility shift assay (EMSA), and the chromatin immunoprecipitation (ChIP) assay in HuH7 cells and also using the mouse liver in vivo. We found that the transcriptional activity of the PFK2/FBP2 gene was stimulated by insulin and inhibited by cAMP and glucocorticoid. Liver X receptor (LXR) α showed a potent and specific stimulatory effect on PFK2/FBP2 gene transcription. Deletion and mutagenesis analyses identified the LXR response element (LXRE) in the 5'-promoter region of the PFK2/FBP2 gene. Binding of LXRα was confirmed by the EMSA and ChIP assay. Endogenous PFK2/FBP2 mRNA in the mouse liver was increased in the fasting/refeeding state compared with the fasting state. Altogether, PFK2/FBP2 gene transcription is found to be regulated in a way that is more similar to other glycolytic enzyme genes than to gluconeogenic genes. Furthermore, our data strongly suggest that LXRα is one of the key regulators of PFK2/FBP2 gene transcription.

Regulation of glucocorticoid receptor transcription and nuclear translocation during single and repeated immobilization stress.

We have previously reported reduced glucocorticoid receptor (GR) mRNA levels in the hippocampus and hypothalamic paraventricular nucleus (PVN) during repeated immobilization, which is potentially associated with persistent activation of the hypothalamic-pituitary-adrenocortical axis. We used in situ hybridization and Western blot to examine the transcriptional regulation of the GR gene, GR nuclear translocation, and expression of cytosolic heat shock protein 90 (hsp90), a chaperone protein essential for GR nuclear translocation, in the hippocampus, PVN, and anterior pituitary (AP) during single immobilization (sIMO) and the final immobilization on d 7 after daily IMO for 6 days (rIMO). As with GR mRNA, GR heteronuclear RNA levels decreased in the hippocampus and PVN and increased in the AP during sIMO and rIMO, indicating that the GR mRNA levels in these regions were regulated at the transcriptional level. In both sIMO and rIMO, nuclear GR levels were significantly increased in the hippocampus, medial basal hypothalamus (MBH), and AP. However, GR nuclear translocation was reduced in the hippocampus, unchanged in the MBH, and enhanced in the AP during rIMO, as compared with sIMO. Cytosolic hsp90 expression was unchanged in the hippocampus and MBH, whereas it significantly increased in the AP at 30 min during rIMO but not during sIMO. These results suggest that the site-specific changes in GR nuclear translocation during sIMO vs. rIMO are partially linked to hsp90 responses to immobilization. The reduced nuclear translocation of GR in the hippocampus during rIMO may reflect decreased glucocorticoid-mediated negative feedback on the hypothalamic-pituitary-adrenocortical axis.