Nuclear STAT3 translocation in guinea pig and rat brain endothelium during systemic challenge with lipopolysaccharide and interleukin‐6

Abstract

During systemic inflammation, cytokines are released by immune-competent cells into the circulation, which in turn signal the brain to mediate brain-controlled signs of illness. Cytokine-responsive brain cells can be mapped by histological analysis of cytokine-induced transcription factors or transcription factor-associated molecules revealing different cell phenotypes that respond to activation of the immune system. Critical sites mediating cytokine-dependent immuneffector functions can be divided into two groups, one group of responding cells situated along a tight blood-brain barrier (BBB), and a second cell group in structures with an open BBB, e.g., the sensory circumventricular organs (CVOs). Previous reports from our group suggest that activation of the signal transducer and activator of transcription factor 3 (STAT3) during lipopolysaccharide (LPS)-induced systemic inflammation is mediated by interleukin-6 (IL-6) and occurs in astrocytes of the rat CVOs. Here we show in the guinea pig a time-dependent marked LPS-induced STAT3 activation within astrocytes and endothelial cells of the CVOs, within astrocytes located in brain structures with a functional BBB and within the brain endothelium of the entire brain. In addition, systemic treatment of rats with either rat recombinant IL-6 or LPS induced STAT3 activation in brain endothelial cells in a similar way as observed in the guinea pig brain, stressing the involvement of IL-6 in this phenomenon in a more generalized way. The STAT3-activated brain cells are located in critical target structures mediating cytokine action during LPS-induced inflammation. STAT3-controlled transcriptional activation with yet unknown cell-specific functional consequences seems to be involved in this process.

Circulating interleukin-6 induces fever through a STAT3-linked activation of COX-2 in the brain

“…This was confirmed by our recent study showing that nuclear STAT3 translocation following LPS treatment in guinea pigs occurs only after plasma concentrations of IL-6 reach a critical level (50), also suggesting that LPS-induced STAT3 activation is IL-6 dependent. We have now confirmed these observations and those of others (19,22,24,51) by demonstrating unequivocally that this is indeed the case. Most importantly, the present study showed that STAT3 activation using the paradigms described occurred in endothelial cells lining the vasculature of the brain, adding support to previous observations that these cells constitute important targets for circulating pyrogens (36).…”

“…Recent evidence, however, suggests that COX-2 induction, at least in peripheral tissue, such as the myocardium, can indeed be activated through this pathway (63). In the brain, studies have now shown that systemically administered IL-6 can induce nuclear STAT3 translocation in structures implicated in the fever response (22,51), namely endothelial cells lining the vasculature within the blood-brain barrier (BBB) and the sensory circumventricular organs (sCVOs), which lack an intact BBB. The same studies, however, did not address the precise functional consequence of IL-6-mediated genomic activation of these structures, including whether this humoral mediator can trigger PG synthesis.…”

Behavioral fever in ectothermic vertebrates

“…The OVLT belongs to the sensory circumventricular organs (CVOs), which all lack a tight blood-brain barrier but rather present a fenestrated endothelium. Endogenous pyrogens activate nuclear factor-kappa B (NF-kB) (Laflamme and Rivest, 1999) and signal transducer and activator of transcription-3 (STAT3) (Rummel et al, 2005), transcription factors in brain endothelial cells of a particular locus of the POA called the median preoptic nucleus (MnPO). These transcription factors target several genes among which those encoding the cyclooxygenase 2 (COX2) and the microsomal PGE synthase 1 (mPGES1), both involved in the synthesis of prostaglandin (PG) E 2 (PGE 2 ) (Nadjar et al, 2005;Rummel et al, 2005Rummel et al, , 2006.…”

Spatiotemporal nuclear factor interleukin‐6 expression in the rat brain during lipopolysaccharide‐induced fever is linked to sustained hypothalamic inflammatory target gene induction

“…The expression of these target gene proteins is increased through proinflammatory transcription factors, including the signal transducer and activator of transcription 3 (STAT3) and nuclear factor-jB (NFjB). Recently, we and others have used immunohistochemical detection of STAT3 or NFjB to determine IL6 (STAT3)-or LPS/IL1b-induced (NFjB) genomic activation of specific cell types and brain structures during inflammation and have revealed several hypothalamic nuclei that are implicated in the induction of ''sickness'' responses such as fever (Gautron et al, 2002;Harré et al, 2002Harré et al, , 2003Nadjar et al, 2003;Rummel et al, 2004Rummel et al, , 2005Rummel et al, , 2006Rummel et al, , 2008.…”