Effect of pteridine derivatives on intracellular calcium concentration in human monocytic cells

Abstract

Pteridines are heterocyclic compounds which are synthesized and released by human monocytes/macrophages following stimulation by interferonγ. Their concentration in various body fluids proved to be indicative for the stimulation of the cellular immune system, and determination of pteridines has become an important diagnostic tool. We show that pteridine derivatives, namely neopterin (N), 7,8‐dihydroneopterin (NH2), and 5,6,7,8‐tetrahydrobiopterin (BH4) increase intracellular calcium (Cai) in human monocytic cells. Significant increases of Cai, are observed at 10 nmol/l NH2, at 100 nmol/l BH4 and at 1 mol/l N, i.e. at concentrations encountered in vivo. At a concentration of 1 μmol/l, Cai is increased (from a control value of 145 ± 7 nmol/l) to 464 ± 62 nmol/l (NH2), 340 ± 41 nmol/l (BH4) and 344 ± 46 nmol/l (N), respectively. The increase of Cai depends on the presence of extracellular calcium and is likely to be due to activation of a calcium channel. We show that the absence of extracellular calcium or the addition of lanthanum ions to the extracellular fluid fully reverses the pteridine‐induced increase of Cai. According to these observations, pteridines may mimick the effects of other inflammatory mediators on monocytic cells and seem to be involved in the crosstalk of immunocompetent cells.

Inhibitory effect of neopterin on NADPH‐dependent superoxide‐generating oxidase of rat peritoneal macrophages

“…Elevation of the cytosol calcium concentration has also been considered to be an important factor for superoxide generation in phagocytes. Recently, it has been demonstrated that pteridine derivatives such as NP increase intracellular calcium concentration in human monocytes, and it was suggested that they are involved in the regulation of calcium-mediat-ed macrophage activation including superoxide generation [20]. Another important factor for the superoxide generation is protein kinase C (PKC).…”

Gamma Interferon Is Dispensable for Neopterin Production In Vivo

“…Schobersberger et al demonstrated that incubation of vascular smooth muscle cells (VSMCs) with neopterin promotes nitric oxide synthase gene expression and nitric oxide release (29). In addition, neopterin was found to increase intracellular Ca 2ϩ , indicating a direct role in the production of ROS and NO (37). Furthermore, neopterin was found to amplify the secretion of tumor necrosis factor alpha (TNF-␣) by peripheral blood mononuclear cells induced by lipopolysaccharide (LPS), IFN-␥, and interleukin-2 (4) and to stimulate TNF-␣ gene expression as well as TNF-␣ release and nuclear uptake of NF-B in VSMCs (16).…”

Potential role of immune system activation-associated production of neopterin derivatives in humans

“…In THP-1 cells, neopterin was found to increase intracellular Ca 2+ concentrations, indicating a direct role in the production of reactive species [44]. In vitro-studies using cellfree solutions showed that neopterin enhances hydrogen peroxide-and chloramine-T-dependent chemiluminescence.…”