Peripheral challenge with double‐stranded RNA elicits global up‐regulation of cytokine gene expression in the brain

Abstract

It is well established that mediators of peripheral inflammation are relayed to the brain and elicit sickness behavior via neuroinflammatory agents that target neuronal substrates. In the present study, we used double-stranded RNA (dsRNA), a viral replication intermediate, to mimic the acute phase of viral infection. C57BL/6 mice were injected intraperitoneally with 12 mg/kg of synthetic dsRNA, i.e., polyinosinic-polycytidylic acid (PIC). The treatment induced severe sickness behavior in the animals as revealed by the burrowing test performed 6 hr postinjection. PIC challenge also induced up-regulation of mRNA for several cytokines in the brain as determined by real-time quantitative RT-PCR. In all brain regions, i.e., the forebrain, brainstem, and cerebellum, the gene encoding the CXCL2 chemokine featured the most robust up-regulation over the basal level (saline-injected animals), followed by the genes encoding the CCL2 chemokine, interferon-beta (IFNbeta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFalpha), and interleukin-1beta (IL-1beta). The forebrain featured the highest extent of up-regulation of the Ifnb gene, whereas the other genes attained the highest expression in the cerebellum. Most of the genes featured transient up-regulation, with peaks occurring 3-6 hr after PIC challenge. The TNFalpha, CCL2, CXCL2, IFNbeta, and IL-1beta messages remained profoundly up-regulated even at 24 hr. The expression of genes encoding inducible and neuronal nitric oxide synthase (NOS) in the brain was not affected by the peripheral PIC challenge. However, the endothelial NOS message was initially down-regulated and subsequently up-regulated, indicating stimulation of cerebral vasculature.

Prenatal activation of maternal TLR3 receptors by viral-mimetic poly(I:C) modifies GluN2B expression in embryos and sonic hedgehog in offspring in the absence of kynurenine pathway activation

“…At intraperitoneal doses comparable with those used here, increased concentrations of a wide range of inflammation-related chemokine genes has been reported as well as the classical cytokines 50,51 . Similar doses can also promote the CNS expression of interferons-a and b and interleukins IL-1b and IL-6 52,53 as well as TNFa 54,55 .…”

Prior chronic stress induces persistent polyI:C-induced allodynia and depressive-like behavior in rats: Possible involvement of glucocorticoids and microglia

“…It has been demonstrated that systemic administration of polyI:C induces mechanical pain hypersensitivity by activating microglia in the spinal cord in rats [31,49]. It also induces neuroinflammation in the brain, which is characterized by the expression of proinflammatory cytokines such as IL-1β, IL-6 and TNF-α [25,50]. These brain-derived cytokines also decrease nociceptive thresholds [51][52][53][54][55] and induce depressive-like behavior [56][57][58].…”

Immune–neural connections: how the immune system’s response to infectious agents influences behavior

“…Poly I:C administration to mice induces a transient slight increase in core body temperature but a strong sickness behavioral response, assessed as a decrease in LMA and burrowing activity . This sickness response is accompanied by a marked increase in circulating IFN, IL-6 and TNF followed by CNS mRNA expression of the same cytokines and, to a lesser extent, IL-1 albeit IFN is not increased Gandhi et al, 2007;Konat et al, 2009). This cytokine profile is similar to that shown in Fig.2.…”