Brain Endothelial Cells Express Cyclooxygenase-2 during Lipopolysaccharide-Induced Fever: Light and Electron Microscopic Immunocytochemical Studies

Abstract

Cyclooxygenase-2 (COX-2), a key enzyme in the biosynthesis of prostaglandins, is induced in brain blood vessels by pyrogens, and its essential role in fever has been hypothesized. In this study, we determined (1) the type of cells that express cyclooxygenase-2 in brain blood vessels of lipopolysaccharide-treated rats, and (2) the precise relationship between the time course of fever and that of cyclooxygenase-2 protein expression in these cells. Five hours after the lipopolysaccharide injection (100 microg/kg, i.p.), cyclooxygenase-2-like immunoreactive cells were found in the parenchymal and subarachnoidal blood vessels. In these blood vessels, the cyclooxygenase-2-like immunoreactivity was restricted to the perinuclear region of the endothelial cells as revealed by a laser confocal microscopy, double-immunofluorescence staining with an endothelial marker, and immunoelectron microscopy. On the other hand, the cyclooxygenase-2-like immunoreactive cells were distinct from microglia or perivascular/meningeal macrophages as revealed by double immunostaining with macrophage/microglia-specific antibodies. Cyclooxygenase-2-like immunoreactive cells were first found at 1.5 hr after the lipopolysaccharide injection, at which time the fever had not been developed. After that, the number of cyclooxygenase-2-like immunoreactive cells and fever followed a similar time course, both being highest at 5 hr after the lipopolysaccharide injection and both returning to the baseline by 24 hr. These results demonstrate that brain endothelial cells are the primary sites where the activation of arachidonic acid cascade takes place during fever after intraperitoneal injection of lipopolysaccharide.

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

“…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.…”

“…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.…”

COX-2 inhibition attenuates anorexia during systemic inflammation without impairing cytokine production

“…After LPS administration, it has previously been found that COX-2 mRNA and protein are induced within the central nervous system (CNS), predominantly in vascular endothelium, but also in specific neuronal populations (4,24) as well as peripheral tissues (9,11,22,26). Prominent induction of COX-2 mRNA has been noted specifically within the parenchyma of the hypothalamic paraventricular nucleus (15).…”

Behavioral fever in ectothermic vertebrates

“…PGE 2 is considered as a major pyrogenic mediator of fever (Engstrom et al, 2012;Matsumura et al, 1998;Yamagata et al, 2001). The role of PGE 2 in induction of fever in mammals was already reported in 1971 by Milton and Wendlandt (1971) who demonstrated that microinjection of PGE 2 into the third ventricle of conscious cats and rabbits cause a rise of body temperature.…”