Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1β: a possible site of prostaglandin synthesis responsible for fever

Cao, Chunyu; Matsumura, Kiyoshi; Yamagata, Kanato; Watanabe, Yasuyoshi

doi:10.1016/0006-8993(96)00575-6

Cited by 300 publications

(226 citation statements)

References 39 publications

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“…We and others have reported COX-2 mRNA expression exclusively within the cerebral endothelium in models of LPS, IL-1b or sterile systemic inflammation. 4,[11][12][13][14][15][16][17]20,21,23 In addition, colocalization of both mPGES-1 and COX-2 enzymes within brain endothelial cells was also observed, 18,36 and such results have yet to be reported in perivascular cells. Finally, COX-2 induction was localized to both endothelial and perivascular microglia in response to low doses of i.p.…”

Section: Discussionmentioning

confidence: 93%

“…10 Although COX-2 and mPGES-1 transcriptional activation takes place in cells of the BBB in various models of systemic inflammation, 4,11 the main cell type expressing these transcripts and producing PGE 2 is still under debate. Indeed, whereas numerous studies have provided evidence that both COX-2 and mPGES-1 transcripts and proteins are upregulated within the endothelium of the cerebral capillaries and venules, [12][13][14][15][16][17][18][19][20][21][22][23] other well-performed studies have shown that perivascular cells of hematopoietic origins play a key role in PGE 2 delivery in response to systemic inflammatory stimuli. [24][25][26] Finally, recent findings suggest that stimulation of both types of cells is required to activate the HPA axis during endotoxemia 27 and either types could mediate different phases of CNS activation.…”

Section: Introductionmentioning

confidence: 99%

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MyD88 signaling in brain endothelial cells is essential for the neuronal activity and glucocorticoid release during systemic inflammation

Gosselin

Rivest

2008

Mol Psychiatry

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Activation of neuronal circuits involved in the control of autonomic responses is critical for the host survival to immune threats. The brain vascular system plays a key role in such immune-CNS communication, but the signaling pathway and exact type of cells within the blood-brain barrier (BBB) mediating these functions have yet to be uncovered. To elucidate this issue we used myeloid differentiation factor 88 (MyD88)-deficient mice, because these animals do not show any responses to the cytokine interleukin-1b (IL-1b). We created chimeric mice with competent MyD88 signaling in either the BBB endothelium or perivascular microglia of bone marrow origin and challenged them with IL-1b. Systemic treatment with the cytokine caused a robust transcriptional activation of genes involved in the prostaglandin E 2 (PGE 2 ) production by vascular cells of the brain. Upregulation of these genes is dependent on a functional MyD88 signaling in the endothelium, because MyD88-deficient mice that received bone marrow stem cells from wild-type animals (for example, functional perivascular microglia) exhibited no response to systemic IL-1b administration. MyD88 competent endothelial cells also mediate neuronal activation and plasma release of glucocorticoids, whereas chimeric mice with MyD88-competent perivascular microglia did not show a significant increase of these functions. Moreover, competent endothelial cells for the gene encoding Toll-like receptor 4 (TLR4) are essential for the release of plasma corticosterone in response to low and high doses of lipopolysaccharide. Therefore, BBB endothelial cells and not perivascular microglia are the main target of circulating inflammatory mediators to activate the brain circuits and key autonomic functions during systemic immune challenges.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

MyD88 signaling in brain endothelial cells is essential for the neuronal activity and glucocorticoid release during systemic inflammation

Gosselin

Rivest

2008

Mol Psychiatry

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“…Whether this could produce some isoform selectivity for aspirin at low concentrations of hydroperoxide deserves investigation. Certainly, however, isoform selectivity in humans can not be great in normal physiologic conditions because the clear antipyretic effect of aspirin indicates an inhibition of PGHS-2, based on the evidence that fever is a consequence of PGHS-2 derived PGE 2 biosynthesis [37][38][39].…”

Section: Discussionmentioning

confidence: 99%

Acetylation of prostaglandin H2 synthases by aspirin is inhibited by redox cycling of the peroxidase

Bala

Chin

Logan

et al. 2008

Biochemical Pharmacology

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Aspirin exerts its unique pharmacological effects by irreversibly acetylating a serine residue in the cyclooxygenase site of prostaglandin-H 2 -synthases (PGHSs). Despite the irreversibility of the inhibition, the potency of aspirin varies remarkably between cell types, suggesting that molecular determinants could contribute to cellular selectivity. Using purified enzymes, we found no evidence that aspirin is selective for either of the two PGHS isoforms, and we showed that hydroperoxide substrates of the PGHS peroxidase inhibited the rate of acetylation of PGHS-1 by 68%. Using PGHS-1 reconstituted with cobalt protoporphyrin, a heme devoid of peroxidase activity, we demonstrated that reversal by hydroperoxides of the aspirin-mediated acetylation depends upon the catalytic activity of the PGHS peroxidase. We demonstrated that inhibition of PGHS-2 by aspirin in cells in culture is reversed by 12-hydroperoxyeicosatetraenoic acid dose-dependently (ED 50 = 0.58 ± 0.15 μM) and that in cells with high levels of hydroperoxy-fatty acids (RAW264.7) the efficacy of aspirin is markedly decreased as compared to cells with low levels of hydroperoxides (A549; IC 50 s = 256 ± 22 μM and 11.0 ± 0.9 μM, respectively). Together, these findings indicate that acetylation of the PGHSs by aspirin is regulated by the catalytic activity of the peroxidase which yields a higher oxidative state of the enzyme.

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“…Interleukin-1␤ is a large molecular weight protein, and because of its size and hydrophilicity, it is not believed to cross the blood-brain barrier either by simple diffusion or saturable carriermediated transport mechanisms (Banks et al, 1989, Banks et al, 1991. Instead, it is generally thought that systemic IL-1␤ signals may reach the brain by acting on type 1 IL-1 receptors located on or closely associated with blood vessels within the NTS as well as the nearby area postrema and VLM (Wong and Licinio, 1994;Yabuuchi et al, 1994;Ericsson et al, 1995;Van Dam et al, 1996), resulting in the local production of prostaglandins, which diffuse away to activate nearby cells in these regions (Breder and Saper, 1996;Cao et al, 1996;Elmquist et al, 1997;Ericsson et al, 1997;Buller et al, 1998). However, in the case of the CeA, this series of events does not hold, because inhibition of prostaglandin synthesis does not affect the CeA cell response to systemic IL-1␤ (Buller et al, 1998).…”

Section: Putative Mechanisms For Cea Cell Recruitment By Systemic Il-1␤mentioning

confidence: 99%

“…This notion stems from knowledge that IL-1␤ does not cross the blood-brain barrier by passive or saturable carrier-mediated transport mechanisms in any significant amount (Banks et al, 1989, Banks et al, 1991. Also, unlike other brain regions recruited by IL-1␤ such as the PVN and brainstem catecholamine cell groups (Breder and Saper, 1996;Cao et al, 1996;Elmquist et al, 1997;Ericsson et al, 1997;Buller et al, 1998), CeA cell recruitment does not appear to depend on the production of secondary signaling molecules such as prostaglandins (Buller et al, 1998). In support of an immune activated afferent pathway to the CeA, we have demonstrated recently that chemical lesions of nucleus tractus solitarius (NTS) cells in the brainstem reduce the number of CeA cells recruited in response to systemic IL-1␤ (Buller et al, 2001).…”

mentioning

confidence: 93%

Systemic administration of interleukin‐1β activates select populations of central amygdala afferents

Buller

Day

2002

J of Comparative Neurology

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The central nucleus of the amygdala (CeA) is activated robustly by an immune challenge such as the systemic administration of the proinflammatory cytokine interleukin-1␤ (IL-1␤). Because IL-1␤ is not believed to cross the blood-brain barrier in any significant amount, it is likely that IL-1␤ elicits CeA cell recruitment by means of activation of afferents to the CeA. However, although many studies have investigated the origins of afferent inputs to the CeA, we do not know which of these also respond to IL-1␤. Therefore, to identify candidate neurons responsible for the recruitment of CeA cells by an immune challenge, we iontophoretically deposited a retrograde tracer, cholera toxin b-subunit (CTb), into the CeA of rats 7 days before systemic delivery of IL-1␤ (1 g/kg, i.a.). By using combined immunohistochemistry, we then quantified the number of Fos-positive CTb cells in six major regions known to innervate the CeA. These included the medial prefrontal cortex, paraventricular thalamus (PVT), ventral tegmental area, parabrachial nucleus (PB), nucleus tractus solitarius, and ventrolateral medulla. Our results show that after deposit of CTb into the CeA, the majority of double-labeled cells were located in the PB and the PVT, suggesting that CeA cell activation by systemic IL-1␤ is likely to arise predominantly from cell bodies located in these regions. These findings may have significant implications in determining the central pathways involved in generating acute central responses to a systemic immune challenge.

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Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1β: a possible site of prostaglandin synthesis responsible for fever

Cited by 300 publications

References 39 publications

MyD88 signaling in brain endothelial cells is essential for the neuronal activity and glucocorticoid release during systemic inflammation

MyD88 signaling in brain endothelial cells is essential for the neuronal activity and glucocorticoid release during systemic inflammation

Acetylation of prostaglandin H2 synthases by aspirin is inhibited by redox cycling of the peroxidase

Systemic administration of interleukin‐1β activates select populations of central amygdala afferents

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