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Angiotensin (Ang) II participates in the pathogenesis of heart failure through induction of cardiac hypertrophy. Ang II-induced hypertrophic growth of cardiomyocytes is mediated by nuclear factor of activated T cells (NFAT), a Ca2+-responsive transcriptional factor. It is believed that phospholipase C (PLC)-mediated production of inositol-1,4,5-trisphosphate (IP3) is responsible for Ca2+ increase that is necessary for NFAT activation. However, we demonstrate that PLC-mediated production of diacylglycerol (DAG) but not IP3 is essential for Ang II-induced NFAT activation in rat cardiac myocytes. NFAT activation and hypertrophic responses by Ang II stimulation required the enhanced frequency of Ca2+ oscillation triggered by membrane depolarization through activation of DAG-sensitive TRPC channels, which leads to activation of L-type Ca2+ channel. Patch clamp recordings from single myocytes revealed that Ang II activated DAG-sensitive TRPC-like currents. Among DAG-activating TRPC channels (TRPC3, TRPC6, and TRPC7), the activities of TRPC3 and TRPC6 channels correlated with Ang II-induced NFAT activation and hypertrophic responses. These data suggest that DAG-induced Ca2+ signaling pathway through TRPC3 and TRPC6 is essential for Ang II-induced NFAT activation and cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

The susceptibility of thermally injured mice (TI-mice) to murine cytomegalovirus (MCMV) infection is markedly influenced by burn-associated type 2 T cell responses, which are common with severe thermal injuries. In the present study, the effect of soluble IL-4 receptor (sIL-4R) on the skin-graft-associated MCMV infection was investigated. The marked growth of MCMV was demonstrated in the salivary glands of TI-mice grafted with MCMV seropositive [MCMV sero(+)] skin. However, the growth of MCMV was not demonstrated in the salivary glands of TI-mice grafted with MCMV sero(+) skin and treated with 50 ng per mouse of sIL-4R. Compared with grafted normal mice, production of type 1 cytokines was markedly decreased when splenic T cells from TI-mice grafted with MCMV sero(+) skin were stimulated with anti-CD3 monoclonal antibody (mAb). The impaired type 1 cytokine production was recovered in cultures of splenic T cells from grafted TI-mice previously treated with sIL-4R. After grafting with MCMV sero(+) skin, the growth of MCMV was markedly inhibited in the salivary glands of severe combined immunodeficient (SCID) mice inoculated with T cells from TI-mice treated with sIL-4R. These results suggest that sIL-4R regulates the skin-graft-associated MCMV infection in TI-mice. [Copyright &y& Elsevier]

In the accompanying paper, the resistance to infections with HSV type 1 (HSV-1) and Candida albicans was improved in thermally injured mice treated with benzoylmesaconine (BEN), an aconitine-hydrolysate isolated from heated Aconiti tuber, or inoculated with splenic CD4+ T cells from BEN-treated mice (BEN T cells). In this paper, therefore, the antiviral mechanism of BEN T cells (or BEN) on the improved resistance of burned mice to the HSV-1 infection was studied. Burn-associated CD8+ CD11b+ TCRγ/δ+ type-2 T cells have been shown to be a key on the increased susceptibility of thermally injured mice to infection with HSV-1 or C. albicans. The susceptibility of T6S-mice, mice inoculated with 1 × 106 cells/mouse of T6S cells (a clone of burn-associated type-2 T cells), to HSV-1 infection was similar to that of thermally injured mice. The adoptive transfer of BEN T cells to T6S-mice restores their impaired resistance to HSV-1 infection. The type-2 cytokine levels in sera of T6S-mice were decreased after inoculation of BEN T cells. BEN T cells inhibited the type-2 cytokine production by T6S cells when they were cocultured in vitro. BEN T cells, characterized as CD4+ CD28+ TCRα/β+ Vicia villosa (VV) lectin-adherent T cells, showed non-specific ability to inhibit the cytokine production by various type-2 T cells. From the results of the cytokine-producing profile, BEN T cells were shown to be a different subset of CD4+ T cells from Th1 and Th2 cells, although these three CD4+ T cells had similar properties phenotypically. BEN T cells were induced in normal mice 1–4 days after the oral treatment of BEN (1 μg/kg or more). These results suggest that, through the induction of antagonistic CD4+ T cells against burn-associated type-2 T cells, BEN may improve the resistance of T6S-mice (or thermally injured mice) to the... [ABSTRACT FROM AUTHOR]

Experience with two cases of psittacosis is described here in which the number of γδ T cell receptor-positive T lymphocytes (γδ T cell) in the bronchoalveolar lavage fluid was markedly increased (25.1 and 66.9%) and CD8+ T cells were also increased with reversal of the CD4/CD8 ratio. These values improved to the normal range along with recovery of their radiographical findings. The present findings suggest that γδ T cells may play an important role in protection from lung injury caused by Chlamydia psittaci infection. [ABSTRACT FROM AUTHOR]

Angiotensin II (Ang II) activates multiple signaling pathways leading to hyperplasia of cardiac fibroblasts. Reactive oxygen species (ROS) produced by Ang II stimulation are assumed to play pivotal roles in this process. Here, we show that ROS mediate Ang II-induced activation of nuclear factor of activated T cells (NFAT) in rat cardiac fibroblasts. Ang II-induced NFAT activation was suppressed by diphenyleneiodonium (an NADPH oxidase inhibitor), dominant negative (DN)-Rac, DN-p47phox, and an inhibitor of Gα12/13 (Gα12/13-specific regulator of G protein signaling domain of p115RhoGEF, p115-regnlator of G protein signaling (RGS)). Stimulation of Ang II receptor increased the intracellular ROS level in a Rac- and p47phox-dependent manner. Because p115-RGS suppressed Aug II-induced Rac activation, Aug II receptor-coupled Gα12/13 mediated NFAT activation through ROS production by Rac activation. Aug II-induced nuclear translocation of the green fluorescent protein (GFP)-tagged Amino-terminal region of NFAT4 (GFP-NFAT4) was suppressed by p115-RGS or BAPTA but not by diphenyleneiodonium. The expression of constitutively active (CA)-Gα12, CA-Gα13, or CA-Rac increased the nuclear translocation of GFP-NFAT4. These results suggest that NFAT activity is regulated by both Ca2+-dependent and ROS-dependent pathways. Furthermore, activation of c-Jun NH2-terminal kinase (JNK) induced by Aug II stimulation is required for NFAT activation because Aug II-induced NFAT activation was inhibited by SP600125, a selective JNK inhibitor. These results indicate that Aug II stimulates the nuclear translocation and activation of NFAT by integrated pathways including the activation of Gα12/13, Rac, NADPH oxidase, and JNK and that Gα12/13-mediated ROS production is essential for N-FAT transcriptional activation. [ABSTRACT FROM AUTHOR]