Glucocorticoid receptors are required for up‐regulation of neuronal 5‐lipoxygenase (5LOX) expression by dexamethasone

Abstract

5-lipoxygenase (5LOX) is the key enzyme in the synthesis of leukotrienes from arachidonic acid. Hyperglucocorticoidemia, dexamethasone, and aging up-regulate 5LOX in the brain, including the cerebellum in vivo. We studied the mechanisms of dexamethasone-triggered 5LOX upregulation in primary cultures of rat cerebellar granule neurons (CGN). We measured 5LOX mRNA and protein contents, and the formation of cysteinyl leukotrienes (LTC 4 , LTD 4 , and LTE 4 7KHGH[DPHWKDVRQH0RUµM)-increased 5LOX mRNA and protein contents were already observed at 3 h of treatment, and they persisted for at least 24 h. Dexamethasone also LQFUHDVHG WKH FRQWHQW RI F\VWHLQ\O OHXNRWULHQHV DVVD\HG LQ WKH SUHVHQFH RI 0 FDOFLXP LRQRSKRUH $ DQG 0 DUDFKLGRQLF DFLG 7KH VWimulatory effect of dexamethasone on 5LOX expression was inhibited by the glucocorticoid receptor (GR) antagonist RU486 and by reducing the CGN content of GR receptor protein with a GR-specific antisense oligonucleotide. The 5LOX mRNA half-life was longer in dexamethasone than in vehicle-treated CGNs. Our results indicate that dexamethasone increases 5LOX expression in CGNs in a GR-dependent manner and that it also increases the stability of 5LOX mRNA. Further studies are warranted to elucidate the physiologic/pathologic significance of glucocorticoid-regulated expression of 5LOX in the central nervous system.-Lipoxygenase (5LOX) enzyme activity is crucial for the biosynthesis of inflammatory eicosanoids, leukotrienes (LTs) from arachidonic acid. 5LOX catalyzes the oxygenation of arachidonic acid, leading to formation of 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and its subsequent dehydration into leukotriene A 4 (LTA 4 ). LTA 4 is the precursor for other LTs; that is, LTB 4 and the family of cysteinyl leukotrienes (cysLTs: LTC 4 , LTD 4 , and LTE 4 ) (1). In the brain, increased formation of cysLTs was found in response to seizures (2). Moreover, the brain also expresses a receptor specific for cysLTs, the cysteinyl leukotriene 2 receptor (3). An 5 increased expression of 5LOX during aging was associated with increased brain vulnerability to neurodegeneration (4). Thus, it has been suggested that inflammatory mechanisms, including the 5LOX pathway, might contribute to the pathophysiology of aging-associated brain disorders, such as Alzheimer's disease (5, 6).Recently, we have found that the content of 5LOX mRNA and protein in the central nervous system, including the cerebellum, increases after prolonged (10 days) treatment of rats with glucocorticoids, corticosterone, or dexamethasone (7). However, this rather unsuspected finding that anti-inflammatory hormones (i.e., glucocorticoids) whose secretion is increased in the elderly (8) also increase the expression of a proinflammatory enzyme (i.e., 5LOX) is not without precedent. Thus, it was reported recently that dexamethasone increases 5LOX mRNA and protein in human mast cells (9), and in human peripheral blood monocytes and the acute monocytic leukemia cell line, THP-1 (10). The exact mechanism of glucocorticoid-stimulated ...

Glucocorticoids Sensitize Rat Placental Inflammatory Responses via Inhibiting Lipoxin A4 Biosynthesis1

“…Another crosstalk between the activated forms of aryl hydrocarbon receptor and GR was also reported [42]. Here we found GR was required for ALOX5 activation, consistent with a previous work conducted in neurons [43]. We recently showed that LXA 4 analog partially alleviated Dex-induced IUGR in rats [7], further supporting FIG.…”

Knockout of 5‐lipoxygenase prevents dexamethasone‐induced tau pathology in 3xTg mice

“…Chronic treatment with corticosterone increases message and protein of 5LO in the rat cerebellum, and blockade of the glucocorticoid receptor reduces dexamethasone-induced message and expression of 5LO in cultured primary rat cerebellar granular neurons (Uz et al, 1999; Uz et al 2001), suggesting 5LO expression is directly affected by stress hormones in the brain.…”

The 5-Lipoxygenase as a Common Pathway for Pathological Brain and Vascular Aging

“…The expression of 5-LO is susceptible to hormonal regulation, since higher levels are observed in conditions of melatonin deficiency and/or hyperglucocorticoidemia [10, 11], both of which are common in elderly subjects [12]. Although in general upregulation of 5-LO might serve a physiological purpose, during the aging process, it may also increase the vulnerability of the cardiovascular system and CNS to different insults/stressors [13].…”