CD4+ T helper type 2 (Th2) cells are crucial for mediating allergic inflammatory lung disease such as asthma, by producing key cytokines including interleukin (IL)-4, IL-5 and IL-13. The phytoalexin, resveratrol, which is rich in grapes and red wine, can increase lifespan and has been suggested as a potential reagent to treat aging-related diseases. Herein we report that resveratrol prevents mice from developing experimental asthma induced by ovalbumin sensitization and re-challenge. Feeding mice with resveratrol inhibits the chronic allergic inflammation in lungs and reduces the numbers of eosinophil/neutrophils in bronchoalveolar lavage fluid. The mechanism appears to be resveratrol-induced suppression of allergic lung inflammation by inhibition of Th2-cytokine production. OVA-specific IL-5 and IL-13 production by CD4+ T cells in treated mice is reduced. Indeed, resveratrol blocks the in vitro polarization of naïve CD4+ T cells to the Th2 phenotype. Western blotting analysis further shows that resveratrol specifically down-regulates the expression of the Th2 transcription factor, GATA-3. These results suggest that resveratrol has therapeutic potential for altering the course of allergic inflammatory lung diseases such as asthma.

Duchenne muscular dystrophy (DMD) affects both skeletal and cardiac muscle. It is currently unclear whether the strategies developed for skeletal muscle can ameliorate cardiomyopathy. Synthetic mini-/micro-dystrophin genes have yielded impressive skeletal muscle protection in animal models. The 6-kb DeltaH2-R19 minigene is particularly promising because it completely restores skeletal muscle force to wild-type levels. Here, we examined whether expressing this minigene in the heart, but not skeletal muscle, could normalize cardiac function in the mdx model of DMD cardiomyopathy. Transgenic mdx mice were generated to express the DeltaH2-R19 minigene under the control of the alpha-myosin heavy-chain promoter. Heart structure and function were examined in adult and very old mice. The DeltaH2-R19 minigene enhanced cardiomyocyte sarcolemmal strength and prevented myocardial fibrosis. It also restored the dobutamine response and enhanced treadmill performance. Surprisingly, heart-restricted DeltaH2-R19 minigene expression did not completely normalize electrocardiogram and hemodynamic abnormalities. Overall, systolic function and ejection fraction were restored to normal levels but stroke volume and cardiac output remained suboptimal. Our results demonstrate that the skeletal muscle-proven DeltaH2-R19 minigene can correct cardiac histopathology but cannot fully normalize heart function. Novel strategies must be developed to completely restore heart function in DMD.

Serum amyloid A-activating factor-1 (SAF-1) is a zinc finger transcription factor that is activated by many mediators of inflammation including IL-1, IL-6, and bacterial LPS. However, the mechanism of activation is not fully understood. To identify possible activation partners for SAF-1, we used a yeast two-hybrid system that detected interaction between the catalytic subunit of cyclic AMP-dependent protein kinase (PKA-Cα) and SAF-1. Immunofluorescence and combined immunoprecipitation-Western blot analyses revealed colocalization and interaction between SAF-1 and PKA-Cα. In vivo evidence of SAF-1 and PKA-Cα interaction was further revealed by coimmunoprecipitation of these two proteins in cAMP-activated liver cells. We further show that SAF-1 is phosphorylated in vitro by PKA-Cα and that addition of cAMP markedly induces in vivo phosphorylation of SAF-1 and transcription of SAF-regulated reporter genes. These results showed that SAF1-PKA-Cα interaction is involved in functional activation of SAF-1.