Knockouts of SOD1 and GPX1 exert different impacts on murine islet function and pancreatic integrity.

Metabolic subtlety and clinical relevance of different forms of reactive oxygen species in diabetes remain unclear. Using single knockout of Cu,Zn-superoxide dismutase (SOD1(-/-)) or Se-glutathione peroxidase-1 (GPX1(-/-)) and their double-knockout (DKO) mouse models, we determined if elevating endogenously-derived superoxide and hydroperoxide exerted distinct impacts and mechanisms on body glucose homeostasis. Whereas the three knockout groups displayed decreased plasma insulin concentrations and islet ß-cells mass, only SOD1(-/-) showed decreased body weight, increased blood glucose, and blocked glucose-stimulated insulin secretion. Null of SOD1 and GPX1 elevated respective islet superoxide and hydroperoxide production, and upregulated p53 phosphorylation. Knockout of SOD1 downregulated the foxhead box A2/pancreatic and duodenal homeobox 1 pathway in a superoxide-dependent fashion at epigenetic, mRNA, and protein levels in islets, but improved insulin signaling in liver and muscle. The SOD1(-/-) mice showed more apparent pancreatitis than the GPX1(-/-) mice that were more susceptible to the cerulein-induced amylase increase. Knockout of SOD1 impaired islet function, pancreas integrity, and body glucose homeostasis more than that of GPX1. Simultaneous ablation of both enzymes did not result in additive or aggravated metabolic outcomes.

Critical role for apoptosis signal-regulating kinase 1 in the development of inflammatory K/BxN serum-induced arthritis.

In this report, we show that apoptosis signal-regulating kinase 1(-/-) (ASK1 KO) mice were resistant to inflammatory arthritis induced in the K/BxN serum transfer model of rheumatoid arthritis (RA). The p38 inhibitor, SD-0006 was administered to wild type (WT) mice as a comparator. Both ASK1 KO and p38 inhibition resulted in marked attenuation of edema, cartilage damage, bone resorption, and general inflammatory responses. Transcriptional profiling of mRNA prepared from paw tissue demonstrated that the production of many proinflammatory genes including cytokines, chemokines, and extracellular matrix degradative enzymes were maintained at basal levels by either ASK1 KO or prophylactic p38 MAPK inhibition. In the mouse whole blood (MWB) assay, tumor necrosis factor-α (TNF-α)-induced KC and CCL2 levels and also LPS-induced interleukin-6 (IL-6), CCL2, and KC levels in MWB from ASK1 KO were significantly lower than those from WT. Furthermore, both p38 and JNK were activated by TNF-α in human synovial fibroblasts isolated from RA patients (RASF). SD-0006 or SP600125, a JNK inhibitor, partially blocked the elevation of IL-6 production in RASF following stimulation with TNF-α. In contrast, dual inhibition with both p38/JNK inhibitors almost completely abolished TNF-α-induced IL-6 production from these cells. Ablation of ASK1 expression in RASF using siRNA for ASK1 resulted in inhibition of TNF-α-induced IL-6 and PGE(2) production. This study is the first to suggest that ASK1 is critical for the development of RA and that ASK1 may be involved in the production of proinflammatory mediators in response to TNF-α stimulation in the RA joint.