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)

We examined whether L-arginine is a substrate for nitric oxide (NO) production by peripheral blood mononuclear cells (MNC) in vitro. Minimal extracellular arginine (0.04 mmol/L) is required for maximal lymphocyte proliferation after phytohemagglutinin stimulation. In the absence of arginine, proliferation was 41% of normal without loss of viability. In contrast, MNC total protein synthesis (as assessed by tritiated leucine incorporation) or lymphokine synthesis (interleukin-2, as assessed by cytotoxic lymphoid line (CTLL) proliferation) were not affected by the absence or presence of arginine in the medium. Exogenous nitric oxide provided as sodium nitroprusside could replace L-arginine for maximal blastogenic proliferation. The addition of NG-monomethyl-L-arginine (NMMA; 0.1 mmol/L), a specific inhibitor of the NO synthetic pathway, significantly reduced DNA synthesis both at 0 and 0.1 mmol/L arginine concentrations; this effect was reversed to 91% of normal by excess arginine (1.0 mmol/L). Homoarginine (0.1 mmol/L; a known substrate for NO production) partially substituted for arginine, and this effect was also abrogated by NMMA. Nitrite levels (an end product of NO metabolism) were reduced when L-arginine was absent or NMMA was added to L-arginine-containing media. Cytosol from phytohemagglutinin-stimulated MNC-enhanced cyclic guanosine monophosphate production in the presence of L-arginine as substrate. The data suggest that the inductive effects of L-arginine on MNC DNA synthesis are not related to its nutrient requirement for protein synthesis, but rather caused by its role as a substrate for NO production. MNC actively synthesize NO during mitogenic proliferation. NO appears to be a promoter of MNC DNA synthesis, probably by its well-known effect as an activator of guanylate cyclase, which increases cyclic guanosine monophosphate levels.
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PMID:Nitric oxide generation from L-arginine is required for optimal human peripheral blood lymphocyte DNA synthesis. 185 40

Leukotrienes B4, C4, and D4 were capable of replacing the helper cell or interleukin 2 requirement for gamma-interferon (IFN gamma) production by Lyt-1-,2+ cells from C57BL/6 mouse spleen cells at leukotriene concentrations as low as 0.002 microM. An antioxidant inhibitor (butylated hydroxyanisole) of lipoxygenase metabolism of arachidonic acid suppressed IFN gamma production. The suppression was significantly reversed by leukotriene C4, which further suggests that leukotrienes and possibly other substances produced by the lipoxygenase pathway of arachidonic acid metabolism play an important role in the regulation of IFN gamma production. All of these events may be related to activation of guanylate cyclase activity, since cyclic GMP also significantly reversed the suppressor effects of butylated hydroxyanisole in IFN gamma production. The leukotriene help for IFN gamma production was independent of DNA synthesis or cellular proliferation. The data are consistent with the hypothesis that lipxoygenase products of arachidonic acid metabolism may play a role in the mediation of interleukin 2 help in IFN gamma production. Cells that are rich sources of leukotrienes, then, should play important roles in positive regulation of lymphokine production.
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PMID:Leukotrienes: positive signals for regulation of gamma-interferon production. 631 47

BM 12,531 (azimexon) is an experimental immunomodulating agent which augments cellular immune responses in vivo. This study indicates that BM 12,531, while not directly mitogenic for human peripheral blood lymphocytes nor guinea pig peritoneal macrophages, potentiates the proliferative effects of phytohemagglutinin and a lymphokine, respectively. The optimal effects (0.001--0.01 microgram/ml) are somewhat greater in magnitude than those of levamisole. Unlike levamisole, BM 12,531 has no effect on cyclic 3',5' GMP levels or on guanylate cyclase activity of lymphocytes. The data suggest that both the thymus-derived lymphocyte and the monocyte-derived macrophage are cell targets of BM 12,531 action at concentrations achievable in vivo.
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PMID:Effects of BM 12,531 (azimexon) on in vitro lymphocyte and macrophage proliferation. 723 28