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

Chapman, Karen; Coutinho, Agnes E.; Gray, Mohini; Gilmour, James S.; Savill, John; Seckl, Jonathan R.

doi:10.1016/j.mce.2008.09.031

Cited by 69 publications

(48 citation statements)

References 135 publications

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“…Only the recent data of Ignatova et al [38] indicate the role of p38 MAPK-mediated regulation of 11HSD1 in the presence of TNF-␣. Relatively little is known about 11HSD1, particularly in immune cells [29], but it is conceivable that cytokines modulate 11HSD1 transcription. In airway smooth muscle, IL-13 caused the upregulation of 11HSD1 via the activation of AP-1 coupled to MAPK signaling via the ERK1/2 and JNK pathways [40].…”

Section: Discussionmentioning

confidence: 99%

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

Ergang

Vytáčková

Švec

et al. 2011

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Discussionmentioning

confidence: 99%

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

Ergang

Vytáčková

Švec

et al. 2011

The Journal of Steroid Biochemistry and Molecular Biology

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“…High expression of 11␤-HSD1 in M1 macrophages may promote the subsequent transition to a phagocytic phenotype, thus promoting resolution of inflammation. 11␤-HSD1 is markedly downregulated following phagocytosis of apoptotic leukocytes (115). Dashed lines indicate speculative connections, whereas solid lines have been demonstrated.…”

Section: ␤-Hsd2mentioning

confidence: 97%

“…The relevance of these in vitro defined phenotypes to the situation in vivo is unclear (171), although the dynamic regulation of 11␤-HSD1 by various stimuli suggests it shapes macrophage phenotype during the inflammatory response (231, 454). Phagocytosis of apoptotic neutrophils by macrophages which promotes resolution of inflammation, decreases 11␤-HSD1, suggesting an active process (115).…”

Section: ␤-Hsd1mentioning

confidence: 99%

“…Again levels depend on cell state. Neutrophil expression of 11␤-HSD1 (336) is increased during inflammation (137) but is absent in apoptosis (115). Neutrophil number and apoptosis de-pend on glucose shuttling between the cytoplasm and ER (119), and perhaps 11␤-HSD1 alters because of coupling to H6PDH.…”

Section: ) 11␤-hsd1 Induction Accompanies Dendritic Cell Differenmentioning

confidence: 99%

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11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Chapman

Holmes

Seckl

2013

Physiological Reviews

734

601

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Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

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“…They achieve this by altering gene transcription and altering pro and anti-infl ammatory mediators including cytokines and signaling pathways. 11β (Beta)-HSD1 is believed to play a key role in local infl ammation and immune response to stimuli and allergens [ 108 ].…”

Section: Infl Ammation and Immunitymentioning

confidence: 99%

The Dehydrogenase Hypothesis

Woods

Tomlinson

2015

Advances in Experimental Medicine and Biology

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Circulating glucocorticoid (GC) levels are controlled by the Hypothalamo-Pituitary-Adrenal (HPA) axis, but within tissues, GC availability is controlled by the isoforms of 11β (Beta)-Hydroxysteroid Dehydrogenase 11β (Beta)-HSD that interconvert inactive cortisone and active cortisol. Two isoforms have been identified; in key metabolic target tissues (including liver and adipose), expression of 11β (Beta)-HSD1 predominates that in vivo converts cortisone to cortisol and thus amplifies local GC action. In contrast, in mineralocorticoid target tissues 11β (Beta)-HSD2 is the isoform that is most abundantly expressed. This inactivates cortisol to cortisone and offers protection for the mineralocorticoid receptor form occupation and activation by cortisol. Dysregulated 11β (Beta)-HSD1 activity has been implicated in many metabolic diseases such as obesity and diabetes and inhibition of 11β (Beta)-HSD1 represents a promising therapeutic target. Mutations within the gene encoding 11β (Beta)-HSD2 cause the Syndrome of Apparent Mineralocorticoid Excess and decreases in activity are linked to hypertension as well as impairment in placental function and neonatal growth. We will discuss the molecular biology and enzymology of 11β (Beta)-HSD and its role in normal physiology and discuss altered 11β (Beta)-HSD activity in pathological states and the potential for therapeutic targeting.

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

Cited by 69 publications

References 135 publications

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

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

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

The Dehydrogenase Hypothesis

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