Phosphatase and tensin homologue deleted on chromosome ten (PTEN) is part of a complex signaling system that affects a variety of important cell functions. PTEN blocks the action of PI3K by dephosphorylating the signaling lipid phosphatidylinositol 3,4,5-triphosphate. We have used a mouse model for asthma to determine the effect of PI3K inhibitors and PTEN on allergen-induced bronchial inflammation and airway hyperresponsiveness. PI3K activity increased significantly after allergen challenge. PTEN protein expression and PTEN activity were decreased in OVA-induced asthma. Immunoreactive PTEN localized in epithelial layers around the bronchioles in control mice. However, this immunoreactive PTEN dramatically disappeared in allergen-induced asthmatic lungs. The increased IL-4, IL-5, and eosinophil cationic protein levels in bronchoalveolar lavage fluids after OVA inhalation were significantly reduced by the intratracheal administration of PI3K inhibitors or adenoviruses carrying PTEN cDNA (AdPTEN). Intratracheal administration of PI3K inhibitors or AdPTEN remarkably reduced bronchial inflammation and airway hyperresponsiveness. These findings indicate that PTEN may play a pivotal role in the pathogenesis of the asthma phenotype.

No abstract

The ligand-activated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to regulate cell activation, differentiation, proliferation, and/or apoptosis. PPARgamma is also associated with anti-inflammatory responses. However, the signaling mechanism remains elusive. We have used a mouse model for asthma to determine the effect of PPARgamma agonists, rosiglitazone or pioglitazone, and PPARgamma on allergen-induced bronchial inflammation and airway hyperresponsiveness. Administration of PPARgamma agonists or adenovirus carrying PPARgamma cDNA (AdPPARgamma) reduced bronchial inflammation and airway hyperresponsiveness. Expression of PPARgamma was increased by ovalbumin (OVA) inhalation, and the increase was further enhanced by the administration of the PPARgamma agonists or AdPPARgamma. Levels of IL-4, IL-5, IL-13, and eosinophil cationic protein were increased after OVA inhalation, and the increased levels were significantly reduced by the administration of PPARgamma agonists or AdPPARgamma. The results also showed that the administration of PPARgamma agonists or AdPPARgamma up-regulated phosphatase and tensin homologue deleted on chromosome ten (PTEN) expression in allergen-induced asthmatic lungs. This up-regulation correlated with decreased phosphatidylinositol 3-kinase activity as measured by reduced phosphorylation of Akt. These findings demonstrate a protective role of PPARgamma in the pathogenesis of the asthma phenotype through regulation of PTEN expression.

Activation of AMP-activated protein kinase (AMPK), a physiological cellular energy sensor, strongly suppresses cell proliferation in both nonmalignant and tumor cells. This study demonstrates the mechanism of quercetin-induced apoptosis in HT-29 colon cancer cells. Treatment of cells with quercetin significantly decreased cell viability in a dose-dependent manner. Notably, quercetin increased cell cycle arrest in the G1 phase and up-regulated apoptosis-related proteins, such as AMPK, p53, and p21, within 48 h. Furthermore, in vivo experiments showed that quercetin treatment resulted in a significant reduction in tumor volume over 6 weeks, and apoptosis-related protein induction by quercetin was significantly higher in the 100 mg/kg treated group compared to the control group. All of these results indicate that quercetin induces apoptosis via AMPK activation and p53-dependent apoptotic cell death in HT-29 colon cancer cells and that it may be a potential chemopreventive or therapeutic agent against HT-29 colon cancer.

Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step in the degradation of tryptophan and is strongly induced in interferon-␥ (IFN␥)-stimulated dendritic cells (DCs). IDO has recently been established as a key enzyme inT-cell suppression-mediated immune tolerance to tumors. STAT1 phosphorylation appears to play an important role in the control of IDO expression by IFN␥, but the precise regulatory mechanism remains obscure. Here we present a novel mechanism of IFN␥-induced IDO expression in bone marrow-derived dendritic cells. In addition, we demonstrate that curcumin, an active component of turmeric, significantly inhibited the induction of IDO expression and activity by IFN␥. We found that curcumin suppressed STAT1 activation by directly inhibiting Janus-activated kinase 1/2 and protein kinase C␦ phosphorylation in bone marrow-derived DCs, suppressing the subsequent translocation and binding of STAT1 to the GAS element of the IRF-1 promoter. Coincident with these inhibitory effects on IFN␥-induced IDO expression, curcumin reversed IDO-mediated suppression of T-cell responses. Our results, thus, suggest that down-regulation of IDO in DCs is an important immunomodulatory property of curcumin that may be exploited therapeutically in the control of cancers.Dendritic cells (DCs) 3 are professional antigen-presenting cells that function as immune sentinels for the initiation of T-cell responses against microbial pathogens and tumors (1, 2). It is now well known that DCs not only induce immunity but are also important for the induction of T-cell tolerance. In particular, murine CD11c ϩ DCs that coexpress the markers CD8␣, B220, DX5, and DEC205 promote tolerance rather than immunity to specific antigens (3, 4). One of the mechanisms that might contribute to this tolerance in antigen-presenting cells involves the expression of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO).IDO catalyzes the initial and rate-limiting step in the catabolism of tryptophan along the kynurenine pathway. IDO has also recently been established as a key enzyme in T-cell suppression and the induction of immune tolerance (5-7). The expression of IDO by various cell types has broad immunological significance. In particular, in many tumors and tolerant antigen-presenting cells, IDO degrades tryptophan to kynurenine, leading to the depletion of tryptophan and resulting in the suppression of T-cell proliferation (8 -10). Recent in vivo studies suggest that IDO-expressing DCs isolated from tumordraining lymph nodes contribute to the progression of tumors by creating local immunosuppression (11-13).The control of IDO transcription is complex and cell typespecific (6). A number of pathways, including the mitogen-activated protein kinase and noncanonical NF-B signaling pathways as well as the Janus-activated kinase-signal transducer and activator of transcription (JAK-STAT) pathway, can modulate IDO expression in response to a variety of stimuli (14,15). In macrophages and DCs, transcription of the IDO gene is s...