Intratracheal double-stranded RNA plus interferon-γ: A model for analysis of the acute phase response to respiratory viral infections

Traynor, Tim; Majde, Jeannine A.; Bohnet, Stewart; Krueger, James M.

doi:10.1016/j.lfs.2003.10.010

Cited by 75 publications

(46 citation statements)

References 44 publications

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“…Although usually cited for its ability to induce interferons (Toth et al, 1990;Katafuchi et al, 2003;Voss et al, 2006), poly(I:C) is also a strong inducer of IL-1, IL-6, and TNF-␣ (Fortier et al, 2004b;Traynor et al, 2004;Gilmore et al, 2005). Our pilot data suggesting that IL-1␣, TNF-␣, and IFN␥ do not cause behavioral changes in the offspring may be surprising, because these cytokines induce IL-6 in vivo (Gadient and Otten, 1997).…”

Section: Discussionmentioning

confidence: 70%

“…Although it is remarkable that a single intraperitoneal injection of IL-6 is capable of altering the fetal brain, leading to abnormal adult behavior, the cytokine stimulation by poly(I:C) is also quite transient. Poly(I:C)-treated mice display sickness behavior (lethargy, hunched posture, hindlimb stiffness), beginning ϳ30 min after injection and lasting ϳ6 h (data not shown), and a biphasic temperature response consisting of 4 -8 h of hyperthermia followed by 12-24 h of hypothermia (Traynor et al, 2004;Cunningham et al, 2007). However, the effects of poly(I:C) treatment are mild compared with experimental influenza infection, in which sickness behavior and hypothermia last for several days (Yang and Evans, 1961;Shi et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

et al. 2007

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Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism.Key words: schizophrenia; autism; cytokine; poly(I:C); maternal immune activation; IL-6; influenza IntroductionBirth in winter or spring months is an accepted risk factor for schizophrenia, and the preponderance of evidence suggests that the prevalence of influenza in winter months is responsible (Tochigi et al., 2004). Over 25 studies have analyzed schizophrenia incidence after influenza epidemics, and the majority have found an increased incidence among exposed offspring. More recently, Brown and colleagues (Brown and Susser, 2002;Brown et al., 2004;Brown, 2006) examined the medical records of Ͼ12,000 pregnant women and found that second-trimester respiratory infection increases the risk for schizophrenia in the offspring threefold to sevenfold. Because of the high prevalence of influenza infection, they estimate that 14 -21% of schizophrenia cases are caused by maternal infection. These findings are also supported by an association between elevated cytokines or antiinfluenza antibodies in maternal serum and schizophrenia in the offspring (Brown et al., 2004). Maternal infection may also play a role in the pathogenesis of autism (Patterson, 2002). These links are even more remarkable considering that the epidemiological studies are unable to screen for susceptibility genotype. Because of the strong genetic component in autism and schizophrenia, it is likely that only genetically susceptible individuals who were exposed to maternal infection would develop the disorder, suggesting that the risk associated with maternal infect...

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

et al. 2007

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“…In a recent study we found that influenza virus (IV) infection in patients is associated with increased serum levels of the inflammatory cytokine IL-32 and the COX-2-induced prostaglandin PGE 2 . In vitro, IV infection of A549 lung epithelial cells resulted in release of IL-32 and activation of COX-2 expression [1].…”

Section: Introductionmentioning

confidence: 99%

“…In vitro, IV infection of A549 lung epithelial cells resulted in release of IL-32 and activation of COX-2 expression [1]. As a proxy of virus infection we used stimulation of the cells with dsRNA1IFN-g, a combination previously shown to act synergistically when administered intratracheally [2] and in mouse peritoneal macrophages in vitro [3]. We demonstrated that production of IL-32 depends on prior COX-2 activation, but also that IL-32 can exert negative feedback control over activation of COX-2 [1].…”

Section: Introductionmentioning

confidence: 99%

Negative feedback regulation of IL‐32 production by iNOS activation in response to dsRNA or influenza virus infection

Yang

Liu

et al. 2009

Eur J Immunol

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iNOS plays an important role in mediating inflammation. In this study, we found that iNOSderived NO was increased 2.4-fold in the serum samples of 101 patients infected with influenza A virus in comparison with samples of 105 healthy individuals. In A549 human lung epithelial cells, infection with influenza A virus or stimulation with poly(I:C)1IFN-c resulted in increased mRNA and protein levels of both IL-32 and iNOS, with subsequent release of NO. Overexpression of IL-32 resulted in upregulated iNOS expression with subsequent NO production. Knock down of IL-32 by IL-32-specific siRNA resulted in the inhibition of dsRNA-induced expression of iNOS and NO release, indicating that IL-32 is an upstream regulatory factor of dsRNA-triggered iNOS production. Surprisingly, over-expression of iNOS resulted in the reduction of IL-32 expression, and suppression of iNOS by the selective iNOS inhibitor S-methylisothiourea sulfate stimulated IL-32 expression, indicating that a negative feedback mechanism operates between the iNOS/NO and IL-32 systems. These findings suggest that influenza A virus infection activates IL-32 and iNOS expression by a heretofore unrecognized complex mechanism, in which the two pro-inflammatory factors regulate each other, involving positive and negative feedback regulatory loops.Key words: Gene regulation . IL-32 . Inducible nitric oxide synthase . Inflammation . Influenza virus IntroductionIn a recent study we found that influenza virus (IV) infection in patients is associated with increased serum levels of the inflammatory cytokine IL-32 and the COX-2-induced prostaglandin PGE 2 . In vitro, IV infection of A549 lung epithelial cells resulted in release of IL-32 and activation of COX-2 expression [1]. As a proxy of virus infection we used stimulation of the cells with dsRNA1IFN-g, a combination previously shown to act synergistically when administered intratracheally [2] and in mouse peritoneal macrophages in vitro [3]. We demonstrated that production of IL-32 depends on prior COX-2 activation, but also that IL-32 can exert negative feedback control over activation of .In the present study we have pursued the analysis of these inflammatory pathways by testing for activation of the iNOS gene and subsequent production of NO. NO is synthesized from L-arginine by NOS in numerous mammalian cells and tissues and plays a critical role in signal modulation during immune responses, chronic inflammation and carcinogenesis. Three isoforms of NOS have been identified until now: two constitutively expressed and calciumdependent isoforms endothelial NOS and neuronal NOS; one inducible and calcium-independent isoform (iNOS), which catalyzes the production of high amount of NO in response to diverse stimuli [4].Increased IL-32 and iNOS expression stimulated by viral infections has been reported in previous investigations [1,5,6]. However, the function of IL-32 in the pro-inflammatory network is still unclear. Since IL-32 and iNOS are obligatory mediators of inflammation, the Fig. 1D) expression levels in cell ...

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“…LPS, a major component of the outer membrane of gram-negative bacteria, and dsRNA, a viral mimetic, induce a potent inflammatory reaction by activation of several intracellular signaling transduction pathways and leads to the expression of proinflammatory cytokines and chemokines [20][21][22][23]. Addition of LPS or dsRNA to the cells rapidly induces phosphorylation of mitogen-activated protein kinase (MAPK) pathways, p38 and c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases (ERK).…”

Section: Introductionmentioning

confidence: 99%

Induction of lactoferrin gene expression by innate immune stimuli in mouse mammary epithelial HC-11 cells

Limmon

Imani

et al. 2009

Biochimie

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Lactoferrin (LF) is a multifunctional protein. While its functions and mechanism of actions are actively being investigated, the cellular signals that regulate LF expression have not been as explored. We have previously demonstrated that LF is upregulated by estrogen in reproductive system. In this study, we show that the expression of LF was stimulated by bacterial lipopolysaccharide (LPS) and double-stranded RNA (dsRNA) in normal mouse mammalian HC-11 cells. When cells were exposed to either LPS or dsRNA, the mRNA and protein of LF were increased in a dose-and time-dependent manner, yet the kinetics of LF induction by dsRNA or LPS was different. The LPS and dsRNAinduced LF was mainly released into the culture medium where it blocked TNF-α production in exposed cells. We explored the mechanisms of LF induction by LPS and dsRNA using specific inhibitors and found that the induction could be attenuated by inhibitors to PKC, NF-kB, p38 and JNK, but not by an inhibitor to PKA. Interestingly, ERK inhibitor was effective against dsRNA but not against LPS induction of LF. These data suggest that LF was induced by LPS and dsRNA through PKC, NF-kB and MAPK pathways which in turn plays an inhibitory role in the continuation of innate inflammation.

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Intratracheal double-stranded RNA plus interferon-γ: A model for analysis of the acute phase response to respiratory viral infections

Cited by 75 publications

References 44 publications

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

Negative feedback regulation of IL‐32 production by iNOS activation in response to dsRNA or influenza virus infection

Induction of lactoferrin gene expression by innate immune stimuli in mouse mammary epithelial HC-11 cells

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