STAT3 and COX-2 activation in the guinea-pig brain during fever induced by the Toll-like receptor-3 agonist polyinosinic:polycytidylic acid

Abstract

Intra-arterial injections of synthetic double-stranded RNA (polyinosinic:polycytidylic acid, PIPC) at a dose of 500 microg/kg evoked pronounced fever in guinea-pigs. PIPC-induced fever could be antagonized by treatment with the non-selective cyclooxygenase (COX) inhibitor diclofenac and was, in part, attenuated by the administration of the selective COX-2-inhibitor nimesulide (dose: 5 mg/kg for both COX inhibitors). We further investigated whether direct activation of brain cells during PIPC-induced fever could be demonstrated. Using radioactive in situ hybridization, we demonstrated that treatment with PIPC resulted in an upregulation of COX-2 and interleukin-1 beta mRNA in the guinea-pig brain. Thus, COX-2-specific hybridization signals seemed to be mainly associated with brain blood vessels. Intra-arterial injections of PIPC further induced the pronounced nuclear translocation of the transcription factor STAT3 in the endothelium of various fore- and hindbrain areas and in the meninges. In brain structures that lacked a tight blood-brain barrier, i.e. the sensory circumventricular organs (area postrema, vascular organ of laminae terminalis, subfornical organ), the astrocytes and a population of still undetermined cellular phenotype also showed marked STAT3 activation in response to PIPC. The Toll-like receptor-3 agonist PIPC therefore caused a similar activation of brain cells as that reported for other experimental models of systemic inflammation.

Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation

“…To determine whether TLR3-induced febrile responses were intact in the absence of CB 1 receptors, we treated wild-type and CB 1 Ϫ/Ϫ mice with PolyIC. A robust febrile response was observed in both wild-type and CB 1 Ϫ/Ϫ mice similar to that observed in rats (19) and guinea pigs (58). This indicates that TLR3-mediated responses are functional and suggest that COX pathways involved in fever are intact in CB 1 Ϫ/Ϫ mice (58).…”

“…A robust febrile response was observed in both wild-type and CB 1 Ϫ/Ϫ mice similar to that observed in rats (19) and guinea pigs (58). This indicates that TLR3-mediated responses are functional and suggest that COX pathways involved in fever are intact in CB 1 Ϫ/Ϫ mice (58). Furthermore, it is evident that the effector mechanisms responsible for thermogenesis in the CB 1 Ϫ/Ϫ animals are unaffected.…”

“…The innate immune system has the ability to detect many different types of pathogens (2). PolyIC is a double-stranded RNA that is capable of evoking cellular responses via the TLR3 receptor and is used as a model of viral infection (58). Administration of PolyIC to rats evokes a febrile response similar to LPS (15,19).…”

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

“…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. 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).…”

“…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).…”