Something You Haven't Heard About INPP5D

4A). Additionally, IL-1-ra reduced serum IL-1�� compared with untreated CNTg mice (Fig. 4B; P find more We next sought to determine the upstream signalling mechanisms behind IL-1�� processing and release in calcineurin-transgene-induced heart failure. To this end, CNTg mice were bred into the Nlrp3?/? background. Mean echocardiographic measurements are presented in Table 2. Similar to IL-1-ra treatment, we observed an improvement in left ventricular systolic performance in Nlrp3?/? CNTg mice. Fractional shortening was 50 �� 6% in Nlrp3?/? CNTg mice, compared with 33 �� 3% in CNTg mice (Fig. 5B; P INPP5D of maintained myocyte organization and structure, and a reduced mononuclear cellular infiltrate. We assessed activation of the inflammasome in Nlrp3?/? CNTg hearts by Western blotting and serum analysis. Genetic deletion of Nlrp3 produced no changes in ASC or pro-caspase-1 expression (Fig. 6A); however, there was a significant reduction in serum-IL-1�� in Nlrp3?/? CNTg mice compared with CNTg mice (Fig. 6B; P learn more with serum IL-1�� measurements, myocardial activation of pro-caspase-1 was reduced in Nlrp3?/? CNTg hearts, suggesting that IL-1�� intracellular processing occurs downstream of Nlrp3-dependent caspase-1 activation (Fig. 6A). In addition to IL-1�� reduction, Nlrp3?/? CNTg mice had significantly reduced serum TNF-�� compared with CNTg mice (Fig. 6C), consistent with a reduction in systemic inflammation on Nlrp3 and IL-1�� antagonism. We have previously assessed the role of inducible nitric oxide synthase signalling in the cardiac inflammation in CNTg mice, noting an improvement in cardiac structure and function with a resolution of inflammation on genetic ablation of inducible nitric oxide synthase (Somers et al. 2008). There is growing evidence to suggest that a significant component of IL-1��-induced cardiac dysfunction results downstream of inducible nitric oxide synthase (Tatsumi et al. 2000; Csont et al.