Colitis up‐regulates local glucocorticoid activation and down‐regulates inactivation in colonic tissue

Abstract

Colitis induces local glucocorticoid activation from 11-oxo steroids and decreases glucocorticoid inactivation; i.e. inflammation increases local tissue ratio of active and inactive glucocorticoids. The results indicate that the changes in local metabolism of glucocorticoids could contribute to the control of an overshoot of inflammation processes in the colon.

Upregulation of 11β-hydroxysteroid dehydrogenase 1 in lymphoid organs during inflammation in the rat

“…These findings led to the hypothesis that changes in 11HSD activity induced by proinflammatory cytokines might contribute to the feedback regulation of inflammation [8,10,13]. This hypothesis is also supported by the observation that patients with inflammatory bowel diseases [14,15] and animals with experimental colitis [16][17][18][19] downregulate colonic 11HSD2 and upregulate 11HSD1. However, it is not currently known whether proinflammatory cytokines alter 11HSDs in the colon or whether inflammation modulates glucocorticoid metabolism in lymphoid organs.…”

Glucocorticoid Availability in Colonic Inflammation of Rat

“…The finding of decreased 11HSD2 activity in inflamed tissue [15,28] led us to the hypothesis that the local metabolism of glucocorticoids could modulate the inflammation-associated gene expression during colitis. To test this hypothesis, we treated animals with carbenoxolone and measured the metabolism of corticosterone (11HSD1 and 11HSD2), the markers of colonic inflammation (TNF-a, IL-1b, COX-2 and MPO), and the most prominent mucin secreted by intestinal goblet cells (MUC-2).…”

“…The relative mRNA levels of colonic 11HSD1, 11HSD2, and b-actin mRNAs were analyzed as described previously [15]. Briefly, a 1-ll aliquot of the ten-fold diluted RT reaction product was subjected to PCR using a LightCycler instrument (Roche Diagnostics GmbH, Mannheim, Germany); LightCycler-DNA Master Sybr Green I mix; primers, 0.5 lM, MgCl 2 , 3 mM (11HSD1), 4 mM (11HSD2), or 5 mM (b-actin).…”

“…Moreover, some data indicate that the local metabolism of glucocorticoids can be modulated not only by cytokines, but also by glucocorticoids themselves [4,7,14]. As the relationship between locally produced glucocorticoids and inflammation has received only limited attention we examined the influence of modulation of the local metabolism of glucocorticoids by carbenoxolone on the expression of HSD1 and HSD2 and the pro-inflammatory cytokines, cyclooxygenase 2 (COX-2), myeloperoxidase (MPO) and mucin 2 (MUC-2) in inflamed rat colon that showed up-regulation of 11HSD1 and down-regulation of 11HSD2 [15]. The efficacy of carbenoxolone was compared with budesonide, a reference glucocorticoid drug used in the treatment of colitis.…”

The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in the inflammatory response

“…In vivo, 11β-HSD1 expression was rapidly and markedly increased in immune cells elicited in the peritoneum of mice during sterile peritonitis . In human and rodent colitis, colonic 11β-HSD1 was strongly up-regulated and 11β-HSD2 down-regulated (Bryndova et al, 2004;Vagnerova et al, 2006;Zbankova et al, 2007).…”