SHORT COMMUNICATION: Cytokines Induce an L-Arginine-Dependent Effector System in Nonmacrophage Cells

Abstract

Treatment of EMT-6 mammary adenocarcinoma cells with gamma interferon (rMuIFN gamma) plus tumor necrosis factor (rMuTNF alpha) and/or interleukin-1 (rHuIL-1 alpha) causes release of iron-55 label, inhibition of DNA replication, and inhibition of aconitase activity. In addition, the same combinations of cytokines induce EMT-6 cells to synthesize L-citrulline, nitrite, and nitrate directly from L-arginine. Lipopolysaccharide (LPS) can act as a cofactor in the induction of these metabolic effects when added to EMT-6 cells in the presence of rMuIFN gamma. The results show that increased levels of cytokines in the microenvironment can induce a novel effector pathway in somatic cells not specialized for host defense, resulting in specific metabolic effects as well as the inhibition of cellular proliferation.

Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy.

“…The > 75% of predicted), normal bone marrow, and liver and renal func- identified by GC/MS (13)(14)(15)30) electron paramagnetic resonance spectroscopy (21,22) except for nitrogen dioxide (NO2), which was detected by another method (13). The direct synthesis of L-citrulline from L-arginine has been identified with several techniques (12)(13)(14)(15)58). The experiments utilizing L-[guanidino-…”

“…'4C]arginine (13,58) are illustrated in the figure. NO formed by reaction [1] can undergo oxidative degradation in aqueous solution (reactions [2] and [3] or react with nonheme iron associated with sulfur atoms to form nitrosyliron-sulfur complexes (reaction [4]).…”

Cytokine-induced expression of a nitric oxide synthase in rat renal tubule cells.

“…EMT-6 cells, a murine mammary adenocarcinoma, produce micromolar amounts of nitrite and nitrate after cytokine stimulation (21). In addition, cultured hepatocytes obtained from rats injected with Corynebacterium parvum generate -400 nmol nitrate and nitrate/mg protein per 24 h. This nitrate and nitrite production were calcium independent, indicative of NOSi-mediated production of NO (17).…”

Cytotoxicity of Pivoxil Esters of Antiviral Acyclic Nucleoside Phosphonates: Adefovir Dipivoxil Versus Adefovir

“…The concentration of nitrites in supernatants was taken as a measure of NO production 13,14 . It was detected in individual cell-free samples (50 µl) incubated for 10 min at 37 °C with an aliquot of a Griess reagent (1% sulphanilamide/0.1% naphtylendiamine/2.5% H 3 PO 4 ).…”