Nitric oxide produced during murine listeriosis is protective

Abstract

Nitric oxide (NO) has been shown to be important for intracellular microbiostasis in vitro. To determine the role of NO in immune function in vivo, groups of C57BL/6 mice were given a sublethal intravenous inoculum of Listeria monocytogenes EGD, and their urine was monitored daily for nitrate, the mammalian end product of NO metabolism. Urinary nitrate levels peaked at 5 to 10 times the basal level on days 5 to 6, when spleen and liver Listeria counts declined most steeply, and decreased thereafter, when spleens and livers were nearly sterile. Peritoneal macrophages explanted from Listeria-infected mice produced nitrite spontaneously, whereas macrophages from uninfected mice did not. The inducible NO synthase mRNA was detectable in the spleens of infected mice on days 1 to 4 of infection. When Listeria-infected mice were treated orally throughout the infection with N`'-monomethyl-L-arginine (NMMA), a specific NO synthase inhibitor, they showed no detectable rise in urinary nitrate excretion. Mean Listeria counts in the livers and spleens of NMMA-treated mice were 1 to 3 orders of magnitude greater than counts in control mice on days 4 through 8 of infection. Compared with control mice, NMMA-treated mice also showed worse clinical signs of infection, namely, weight loss, hypothermia, decreased food and water intake, and decreased urine output. Histologically, NMMAtreated mice had many more inflammatory foci in their livers and spleens than control mice. The histologic observation that mononuclear cells are present at sites of infection suggests that inhibiting NO production did not block the flux of macrophages into infected viscera. As controls for possible drug toxicity, a group of uninfected mice given NMMA orally showed no detrimental effects on weight, temperature, and food and water intake. These experiments demonstrate that inhibition of NO production in Listeria-infected mice results in an exacerbated infection and thus that NO synthesis is important for immune defense against Listeria infection in mice.

Innate defenses in the liver during Listeria infection

“…Administration of aminoguanidine in vivo effectively reduces endogenous nitric oxide (NO × ), but has no effect on Listeria growth in the first 48 h. By 3 days, however, increases in Listeria burdens are observed (104). Similar results demonstrating NO × -mediated protection are seen in mice lacking the gene for iNOS or treated with NOS inhibitors (96,104,105). Although these studies suggest that RNI are a factor in the antilisterial activity stimulated by IFN-g, in vitro incubation of bacteria with NaNO 2 , NaNO 3 , and gaseous NO × had no detectable effects on Listeria viability (80).…”

Class specific inhibition of house dust mite proteinases which cleave cell adhesion, induce cell death and which increase the permeability of lung epithelium

“…It is noteworthy that the localized trauma and cell death produced by proteolytic cleavage of intercellular junctions may also ful®l some conditions of the`danger model' of adaptive immunological response (Matzinger, 1994;Ridge et al, 1996) and thus explain why allergens evoke antibody-directed responses. In further support of this view, recent evidence has suggested that when apoptosis (previously considered to be an immunologically`silent' form of cell death) occurs in the presence of tissue injury, the resulting combination is a potent stimulus for antigen presenting cells (Boockvar et al, 1994;Casciola-Rosen et al, 1994;Ibrahim et al, 1996).…”

Dramatic differences in the response of macrophages from B2 and B19 MHC-defined haplotypes to interferon gamma and polyinosinic:polycytidylic acid stimulation

“…Macrophages of various chicken lines congenic for MHC have been shown to differ in their chemotactic activity (Qureshi et al, 1988) and recruitment and activation (Qureshi et al, 1986). Like mammalian macrophages, avian macrophages produce nitric oxide (NO) upon activation, killing bacteria or protozoa and inhibiting viral replication (Boockvar et al, 1994;Kreil and Eibl, 1996;MacMicking et al, 1997). Expression of inducible nitric oxide synthase (iNOS) has been shown to differ among chickens of several genotypes, as a result of enhanced transcriptional activity in iNOS hyper-responder genotypes Qureshi, 1997, 1998).…”