Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of exogenous nitric oxide (NO) on the expression of interleukin (IL)-2, IL-4, IL-5 and interferon-gamma (IFN-gamma) by freshly isolated human T lymphocytes was investigated. The presence of NO, generated from any of the NO-donor compounds, S-nitroso-N-acetyl-D,L-penicillamine (SNAP), DPTA-nonoate (DPTA) or DETA-nonoate (DETA), added 15 min prior to T-cell stimulation (for 24 hr) with anti-CD3/anti-CD28 monoclonal antibodies (mAbs), resulted in up to 50% inhibition of IL-4, IL-5 and IFN-gamma secretion. In contrast, IL-2 secretion was not inhibited. Using the guanylate cyclase inhibitor, LY83583, it was shown that the inhibition of IL-4 and IL-5 was cGMP dependent, whereas additional mechanisms mediated the inhibition of IFN-gamma. Exposure of T cells to the NO-donor compounds for 24 hr prior to stimulation resulted in a more pronounced inhibition of IFN-gamma secretion by DPTA and DETA (P < 0.01), despite the fact that NO generation could no longer be detected. Under these conditions, IL-4 secretion was not inhibited and IL-5 secretion was inhibited to a lesser extent (P < 0.01 for SNAP and DPTA, P > 0.05 for DETA). IL-2 secretion was inhibited after 24 hr of preincubation with the NO-donor compounds, whereas it was not directly affected by NO. The increased inhibitory effects on IFN-gamma and IL-2 secretion could not be accounted for by the antiproliferative effects of the NO-donor compounds, which were diminished after 24 hr of preincubation relative to 15 min of preincubation. For IFN-gamma, the inhibition was at least partially effected at the transcriptional level as shown by decreased mRNA accumulation. These data show that NO can modulate the balance between the expression, by human T-lymphocytes, of T helper 1- and T helper 2-type cytokines, through selective and persistent inhibition of the expression of IFN-gamma via a cGMP-independent mechanism.
 ...
PMID:Nitric oxide selectively decreases interferon-gamma expression by activated human T lymphocytes via a cGMP-independent mechanism. 1058 99

Th2 lymphocytes differ from other CD4+ T lymphocytes not only by their effector tasks but also by their T cell receptor (TCR)-dependent signaling pathways. We previously showed that dihydropyridine receptors (DHPR) involved in TCR-induced calcium inflow were selectively expressed in Th2 cells. In this report, we studied whether cGMP-dependent protein kinase G (PKG) activation was implicated in the regulation of DHPR-dependent calcium response and cytokine production in Th2 lymphocytes. The contribution of cGMP in Th2 signaling was supported by the following results: 1) TCR activation elicited cGMP production, which triggered calcium increase responsible for nuclear factor of activated T cell translocation and Il4 gene expression; 2) guanylate cyclase activation by nitric oxide donors increased intracellular cGMP concentration and induced calcium inflow and IL-4 production; 3) reciprocally, guanylate cyclase inhibition reduced calcium response and Th2 cytokine production associated with TCR activation. In addition, DHPR blockade abolished cGMP-induced [Ca2+]i increase, indicating that TCR-induced DHP-sensitive calcium inflow is dependent on cGMP in Th2 cells. Th2 lymphocytes from PKG1-deficient mice displayed impaired calcium signaling and IL-4 production, as did wild-type Th2 cells treated with PKG inhibitors. Altogether, our data indicate that, in Th2 cells, cGMP is produced upon TCR engagement and activates PKG, which controls DHP-sensitive calcium inflow and Th2 cytokine production.
 ...
PMID:The cGMP/protein kinase G pathway contributes to dihydropyridine-sensitive calcium response and cytokine production in TH2 lymphocytes. 1653 16