Nitric Oxide Inhibits Rhinovirus-Induced Granulocyte Macrophage Colony-Stimulating Factor Production in Bronchial Epithelial Cells

Abstract

Infection of asthmatics with human rhinovirus (HRV) enhances airway eosinophilia and airways hyperreactivity. The current studies were performed to further characterize HRV-induced generation by human bronchial epithelial cells of granulocyte macrophage colony-stimulating factor (GM-CSF), a cytokine that could contribute to airway eosinophilia by increasing the survival and activation of eosinophils, and to determine the effects of the antiviral agent nitric oxide (NO) on HRV-induced GM-CSF production. Maximal levels of messenger RNA (mRNA) for GM-CSF were seen 1 h after HRV infection. Expression was sustained through 24 h and declined by 48 h. GM-CSF protein was detected in cell supernatants by 2 h after infection and reached maximal concentrations by 24 h, with the most rapid rate of production occurring from 2 to 7 h. The NO donor 3-(2-hydroxy-2-nitroso-1-propyl-hydrazino)-1-propanamine (NONOate) inhibited HRV-induced GM-CSF protein production in a time- and dose-dependent fashion. NONOate also inhibited HRV-induced GM-CSF mRNA levels at both times (1 and 4 h) examined. NONOate increased GM-CSF mRNA stability, suggesting that reduced mRNA levels were due to inhibition of transcription. The transcription factor nuclear factor-kappa B was rapidly induced by HRV infection, but was not inhibited by NONOate, implying a role for other transcription factors. Thus, NO may play an important anti-inflammatory role in virally induced exacerbations of diseases such as asthma.

Myxoma Virus M141R Expresses a Viral CD200 (vOX-2) That Is Responsible for Down-Regulation of Macrophage and T-Cell Activation In Vivo

“…For example, NO has a demonstrated antiviral effect against viral hemorrhagic septicemia virus, as this fish rhabdovirus's replication was abrogated in the presence of NO donors (50,51). Sanders et al (44,45) demonstrated that nitric oxide is a potent dose-dependent inhibitor of rhinovirus-induced proinflammatory cytokine (granulocyte-macrophage colony-stimulating factor) production. This same group has provided additional evidence that human rhinovirus infections enhance the level of NOS2 expression occurring in epithelial cells, suggesting that the induction of NO is an important factor for clearing this viral infection (46).…”

(R)-Albuterol Elicits Antiinflammatory Effects in Human Airway Epithelial Cells via iNOS

“…Sanders and colleagues (20) elegantly demonstrated that administration of exogenous NO (using the chemical NO donor, NONOate) reduced GM-CSF message and protein levels that were enhanced in human rhinovirus-infected BEAS-2B bronchial epithelial cells via a transcriptionally regulated event. In addition, we have previously demonstrated that GM-CSF expression is increased in NHBE cells in which iNOS is chemically inhibited, suggesting that iNOS plays a role in suppression of GM-CSF expression (38).…”

“…As NO can attenuate production of the proinflammatory cytokine, GM-CSF, in bronchial epithelial cells (20), it is possible that ␤ 2 -adrenergic agonists elicit some of their antiinflammatory properties through an iNOS-mediated pathway. The present study examines the effects of the short-acting ␤ 2 -adrenergic agonist, (R)-albuterol, on expression of iNOS in primary cultures of normal human bronchial epithelial (NHBE) cells in vitro.…”

Chronic Exposure to Innocuous Antigen in Sensitized Mice Leads to Suppressed Airway Eosinophilia That Is Reversed by Granulocyte Macrophage Colony-Stimulating Factor

“…It has been shown that exposure to environmental pollutants, as well as viral and bacterial agents, upregulates GM-CSF production (43)(44)(45)(46). Indeed, these agents have been associated with exacerbation of asthma.…”