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Distribution, regulation and colocalization of the genes encoding the EP 2 ‐ and EP 4 ‐PGE 2 receptors in the rat brain and neuronal responses to systemic inflammation
Author(s) -
Zhang Ji,
Rivest Serge
Publication year - 1999
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.1999.00682.x
Subject(s) - stria terminalis , subfornical organ , area postrema , circumventricular organs , supraoptic nucleus , solitary tract , nucleus , medicine , biology , colocalization , endocrinology , dorsal motor nucleus , hypothalamus , central nucleus of the amygdala , receptor , neuroscience , stimulation , angiotensin ii , vagus nerve
It is currently believed that prostaglandin (PG) of E 2 type plays a crucial role in transferring the information received from circulating immune factors to brain parenchymal cells. Although PGE 2 is synthesized quite essentially by cells of the blood–brain barrier, the organization and regulation of its receptor subtypes within neuronal elements remain unknown. In this study, intravenous (i.v.) injection of the endotoxin lipopolysaccharide (LPS) or recombinant rat interleukin‐1β (IL‐1β), and intramuscular (i.m.) injection of turpentine were used as different models of systemic immune stimuli. Rats were perfused at various times after the insults (30 min to 24 h), their brains cut and hybridized with full‐length rat cRNA probes. Double‐labelling procedures were accomplished to determine the cellular phenotype and activity. A very distinct distribution of both EP 2 and EP 4 receptors was found across the brain under basal conditions; the hybridization signal for the type 2 was detected in the bed nucleus of the stria terminalis (BNST), lateral septum, subfornical organ (SFO), ventromedial hypothalamic nucleus (VMH), central nucleus of the amygdala (CeA), locus coeruleus (LC) and the area postrema (AP), whereas the ventral septal/anterior preoptic area, the magnocellular paraventricular nucleus (PVN), supraoptic nucleus, parabrachial nucleus, LC, the nucleus of the solitary tract (NTS) and the ventrolateral medulla (VLM) exhibited moderate to strong levels for the EP 4 mRNA under basal conditions. Upregulation of the genes encoding EP 2 and EP 4 receptors was detected in selective regions and neuronal populations during systemic inflammatory challenges. The most dramatic one being the robust transcriptional activation of the EP 4 subtype within corticotropin‐releasing factor (CRF) neurons of the parvocellular PVN following i.v. LPS and IL‐1β injection, and the localized i.m. aggression. These neurons of the endocrine hypothalamus as well as those of numerous autonomic‐related nuclei were activated by the proinflammatory cytokine, as they were immunoreactive (ir) to Fos nuclear protein. The EP 4 transcript was also present in activated catecholaminergic neurons of the LC, NTS and VLM, although only the A1 cell group exhibited an increase in EP 4 transcription in response to circulating IL‐1β. Moreover, the systemic immunogenic insults caused a significant increase in the EP 2 mRNA levels in the CeA, SFO, AP and the leptomeninges. These data provide a distinct pattern of EP 2 and EP 4 expression throughout the rat brain under both basal and immune‐challenged conditions, and underlie the possible role of the EP 4 subtype in mediating the effects of PGE 2 on different autonomic and neuroendocrine functions. The presence of Fos‐ir nuclei in various populations of EP 4 neurons of IL‐1β‐treated animals clearly supports this concept and suggests that the selectivity of the neuronal response during systemic inflammation may depend on the expression of specific PGE 2 receptors in key structures of the brain.