Nitric Oxide Inhibits Rhinovirus-Induced Cytokine Production and Viral Replication in a Human Respiratory Epithelial Cell Line

Abstract

To better understand the early biochemical events that occur in human rhinovirus (HRV) infections, we examined the kinetics and mechanisms of interleukin-8 (IL-8) and IL-6 production from infected epithelial cells. Several HRV strains caused IL-8 and IL-6 production, but HRV-16 induced maximal IL-8 and IL-6 mRNA expression and protein production more rapidly than did HRV-14, despite similar rates of replication of the two viral strains. Viral induction of cytokine mRNA does not require new protein synthesis, since it was unaffected by cycloheximide treatment. The potent glucocorticoid budesonide did not affect viral replication or cytokine mRNA induction but modestly inhibited cytokine protein production. Interestingly, the nitric oxide donor 3-(2-hydroxy-2-nitroso-1-propylhydrazino)-1-propanamine (NONOate) inhibited both rhinovirus replication and cytokine production in a dose-dependent fashion without reducing levels of cytokine mRNA. The NONOate effects were due to release of nitric oxide, because NONOate that had been depleted of its nitric oxide content had no effect. Thus, nitric oxide may play an important anti-inflammatory and antiviral role in colds and nitric oxide donors may represent a novel therapeutic approach.

Modulatory effects of ammonia-N on the immune system of Penaeus japonicus to virulence of white spot syndrome virus

“…Nitric oxide produced by NOS is associated with diverse actions in neurotransmission, vascular systems, and immunity, including antimicrobial and antiviral activities by way of inhibiting DNA as well as protein and lipid synthesis (Bredt and Snyder, 1994;Karupiah et al, 1993;Howe et al, 2002;Lepoivre et al, 1990). Thus, the NOS system is a very important component in innate immune system that is related directly to virus killing, such as poliovirus (Ló pez-Guerrero and Carrasco, 1998), picornavirus (Sanders et al, 1998), flavivirus (Kreil and Eibl, 1996), coronavirus (Lane et al, 1997), arenavirus (Campbell et al, 1994), rhabdovirus (Bi and Reiss, 1995), and ACID virus (Raber et al, 1996). As an innate immune effector, NOS can be induced to produce upregulation of NO in many invertebrates by the invasion of bacteria and parasites (Luckhart and Li, 2001;Dimopoulos et al, 2001;Nappi et al, 2000).…”

Virus-induced modulation of lower airway diseases: Pathogenesis and pharmacologic approaches to treatment

“…Understanding the mechanisms by which viruses induce epithelial production of proinflammatory cytokines and chemokines may permit strategies for new therapeutic interventions. In the case of HRV, it is known that some molecules, such as CXCL8 and IL-6, can be induced with virus that has been rendered replication deficient, suggesting that viral binding to its receptor is sufficient to induce production of these cytokines (Sanders et al, 1998). This was surprising, as the receptor for the largest group of HRV family members is intercellular adhesion molecule-1 (ICAM-1) and this receptor has neither endogenous kinase activity nor any known kinase recognition sites (Greenwood et al, 2003).…”

Role of epithelial nitric oxide in airway viral infection

“…Exhaled NO is increased in chronic inflammatory airway diseases, such as asthma and bronchiectasis, and in upper respiratory tract infections, including bacterial and viral respiratory illnesses [21,[43][44][45]. Epithelial cells at mucosal surfaces have a variety of inflammatory and immune defense mechanisms to deal with viruses, including the induction of NOS II and increased production of NO [14][15][16][17][18]29]. For example, experimental influenza virus or rhinovirus 16 infection increase exhaled NO in volunteers [53,54].…”

“…Replication of a wide range of DNA and RNA viruses are inhibited in vitro by the addition of chemical donors of NO, or by the overexpression or induction of NOS II. NO inhibits both virus replication and latency of viruses, including coxsackievirus, influenza A and B, rhinovirus, cytomegalovirus, vaccinia virus, ectromelia virus, human herpesvirus-1, and HPIV3 [18,34,[57][58][59][61][62][63][64][65]. Likewise, loss of NO synthesis leads to increase of virus titers with infection, and significantly more severe clinical outcomes [34,35,60,66,67].…”

“…A critical early component of the innate host defense in the airway is the ability of respiratory epithelial cells to produce high levels of nitric oxide (NO). NO functions as a signaling molecule in initiation of the inflammatory response to viruses, and also has direct antiviral effects [14,[16][17][18]. Here, we review the human airway production of NO and the consequence of NO deficiency on antiviral defense.…”