Fever and circulating cytokines induced by double‐stranded RNA in guinea pigs: dependence on the route of administration and effects of repeated injections

Voss, Thilo; Rummel, Christoph; Gerstberger, Rüdiger; Hübschle, Thomas; Roth, Joachim

doi:10.1111/j.1748-1716.2006.01587.x

Cited by 22 publications

(22 citation statements)

References 39 publications

(96 reference statements)

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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%

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%

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

et al. 2007

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“…Upon activation, these TLRs stimulate the production and release of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α (Dobrovolskaia et al, 2003;Doyle and O'Neill, 2006;Iwasaki and Medzhitov, 2004). Also it has been shown that TLR3 activation can result in the release of interferons (IFN)-α and (IFN)-β (Katafuchi et al, 2003;Toth et al, 1990;Voss et al, 2006). While cytokines are best known for their actions in cell-cell communication between immune cells, they also mediate functions in the non-immune tissues, by binding to cytokine receptors on a wide variety of cells.…”

Section: Animal Models Of Pathogenic Immune Activationmentioning

confidence: 99%

“…Cytokine receptor activation in the periphery and on the vasculature of the brain (Bsibsi et al, 2002) results in activation of NF-κB and AP-1 followed by the production of other mediators including prostaglandins and nitric oxide (Voss et al, 2007). Further synthesis of cytokines in the brain is also observed (Doukas et al, 1994;Katafuchi et al, 2003;Voss et al, 2007;Voss et al, 2006). As a consequence, neurological function is altered, resulting in activation of the hypothalamic-pituitary-adrenal (HPA) axis, and alterations in autonomic outputs (e.g., metabolism) (Dunn, 1988), sensory function (hyperalgesia) (Safieh-Garabedian et al, 2002) and behavior (Nelson et al, 1997).…”

Section: Animal Models Of Pathogenic Immune Activationmentioning

confidence: 99%

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

Rana

Aavani

Pittman

2012

Hormones and Behavior

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Humans are exposed to potentially harmful agents (bacteria, viruses, toxins) throughout our lifespan; the consequences of such exposure can alter central nervous system development. Exposure to immunogens during pregnancy increases the risk of developing neurological disorders such as schizophrenia and autism. Further, sex hormones, such as estrogen, have strong modulatory effects on immune function and have also been implicated in the development of neuropathologies (e.g., schizophrenia and depression). Similarly, animal studies have demonstrated that immunogen exposure in utero or during the neonatal period, at a time when the brain is undergoing maturation, can induce changes in learning and memory, as well as dopaminemediated behaviors in a sex-specific manner. Literature that covers the effects of immunogens on innate immune activation and ultimately the development of the adult brain and behavior is riddled with contradictory findings, and the addition of sex as a factor only adds to the complexity. This review provides evidence that innate immune activation during critical periods of development may have effects on the adult brain in a sex-specific manner. Issues regarding sex bias in research as well as variability in animal models of immune function are discussed.

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“…Previous studies have also shown that the antibodies against adhesion molecules do not affect zymosan-induced inflammation in joints but reduced zymosan-induced peritonitis, suggesting that the characteristics of inflammation are site-specific [42]. It has been demonstrated that, specifically for the febrile response, the route of administration may have an important impact on the kind of mediators generated and their access to the central nervous system [43]. This may also be caused by the access of pyrogens to the cells bearing the specific Toll-like receptor involved.…”

Section: Discussionmentioning

confidence: 99%

“…This may also be caused by the access of pyrogens to the cells bearing the specific Toll-like receptor involved. Voss et al [43] demonstrated that the administration of synthetic RNA into the artificial subcutaneously implanted Teflon chambers, in contrast to LPS, had no pyrogenic activity or cytokine-inducing effects, whereas the i.p. or intra-arterial, and intramuscular injection caused a pronounced or moderated fever and cytokine induction, respectively.…”

Section: Discussionmentioning

confidence: 99%

Central mediators of the zymosan-induced febrile response

Bastos-Pereira

Fraga

Dreifuss

et al. 2017

Journal of Basic and Clinical Physiology and Pharmacology

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Background: Zymosan is a fungal cell wall protein-carbohydrate complex that is known to activate inflammatory pathways through the Toll-like receptors and is commonly used to induce fever. Nevertheless, the central mediators that are involved in the zymosan-induced febrile response are only partially known. Methods:The present study evaluated the participation of prostaglandins, substance P, endothelin-1 (ET-1), and endogenous opioids (eOPs) in the zymosan-induced febrile response by using inhibitors and antagonists in male Wistar rats. Results: Both nonselective (indomethacin) and selective (celecoxib) cyclooxygenase inhibitors reduced the febrile response induced by an intraperitoneal (i.p.) injection of zymosan. Indomethacin also blocked the increase in the prostaglandin E 2 levels in the cerebrospinal fluid. An intracerebroventricular injection of the neurokinin-1, ET B , and μ-opioid receptor antagonists also reduced the febrile response induced by the i.p. injected zymosan. Moreover, the μ-opioid receptor antagonist CTAP also reduced the febrile response induced by intra-articular injection of zymosan.Conclusions: These results demonstrate that prostaglandins, substance P, ET-1, and eOPs are central mediators of the zymosan-induced febrile response.

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Fever and circulating cytokines induced by double‐stranded RNA in guinea pigs: dependence on the route of administration and effects of repeated injections

Abstract: The modulation of the strength of RNA-induced fever, dependent on the route of administration, or the state of partial tolerance to this pyrogen, may thus be related to the formation of pyrogenic cytokines.

Cited by 22 publications

References 39 publications

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

Central mediators of the zymosan-induced febrile response

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