Cellular mechanisms of nonspecific immunity to intracellular infection: Cytokine-induced synthesis of toxic nitrogen oxides from l-arginine by macrophages and hepatocytes

Abstract

Nitric oxide (NO) produced by cytokine-treated macrophages and hepatocytes plays a vital role in protective host responses to infectious pathogens. NO inhibits iron-sulfur-dependent enzymes involved in cellular respiration, energy production, and reproduction. Synthesis of L-arginine-derived nitrite (NO2-), the oxidative end product of NO, directly correlates with intracellular killing of Leishmania major, an obligate intracellular protozoan parasite of macrophages: the level of NO2- production is a quantitative index for macrophage activation. The competitive inhibitor of NO synthesis, monomethylarginine (NGMMLA), inhibits both parasite killing and NO2- production. For Leishmania, the parasite itself participates in the regulation of this toxic effector mechanism. This participation is mediated by parasite induction of tumor necrosis factor alpha (TNF alpha), an autocrine factor of macrophages: NO synthesis by interferon-gamma (IFN-gamma)-treated cells can be blocked by monoclonal antibodies to TNF alpha. NO production by IFN gamma-treated hepatocytes is of special interest in malaria infections: sporozoite-infected hepatocytes kill the intracellular malaria parasite after treatment with IFN gamma; this killing is inhibited by NGMMLA.

Kinetoplastid membrane protein-11 exacerbates infection with Leishmania amazonensis in murine macrophages

“…NO production is an important effector mechanism for the killing of intracellular Leishmania amastigotes by infected macrophages (Green et al 1990, Liew et al 1990). The significant decrease in NO production in the L. amazonensis-infected macrophages treated with KMP-11 (Fig.…”

“…NO is considered to be the principal effector molecule that mediates the intracellular killing of Leishmania amastigotes. Thus, the production of NO is critical for the control of Leishmania infection (Green et al 1990, Soong et al 1996. Some pathogens that infect macrophages, including Leishmania, induce IL-10 production In Leishmania amazonensis, kinetoplastid membrane as an immunosuppressive strategy for survival and replication (Belkaid et al 2001, Redpath et al 2001.…”

N,N-Dimethylacetamide Significantly Attenuates LPS- and TNFα-Induced Proinflammatory Responses Via Inhibition of the Nuclear Factor Kappa B Pathway

“…In fact, MMA resulted in a slightly higher level of NO −2 as compared with the LPS control, although this was not found to be statistically significant. NO is an important inflammatory mediator produced by macrophages and other cells in response to bacterial products like LPS (47)(48)(49). In RAW 264.7 cells, NO is enzymatically produced in the presence of inflammatory stimuli through the induction of iNOS (45,50).…”

Nitric Oxide Sensors for Biological Applications

“…An alternate method of predicting NO concentration within a system is performed by examining upstream components such as NOS activity. First characterized in 1989 [61], NOS is found in three different forms within the body which are named after the location the enzyme was originally discovered: neuronal, inducible, and endothelial NOS (nNOS, iNOS, and eNOS) [62][63][64]. All three isoforms of NOS utilize L-arginine as a substrate, with reduced nicotinamide-adenine-dinucleotide phosphate (NADPH) and oxygen as co-substrates to produce NO and citrulline as a byproduct, as shown in Figure 3 [61,65,66].…”