Sixty Years after Hench—Corticosteroids and Chronic Inflammatory Disease

Abstract

The systemic effects of enhancing 11β-HSD1 activity may amplify the inflammatory response. Thus, increased conversion of cortisone to cortisol can alter the circadian rhythm of cortisol secretion (lower nadir, later rise, impaired stress response) with consequent relative nocturnal cortisol deficiency when inflammatory cytokines are highest. This could contribute to the circadian symptomatology in rheumatoid arthritis, the effectiveness of early morning (0200 h) low-dose corticosteroids, the significant correlation between total body 11β-HSD1 activity and erythrocyte sedimentation rate, and the effectiveness of 11β-HSD inhibition in both the prevention and treatment of adjuvant arthritis in rat models of rheumatoid arthritis. It could also explain why anti-TNF therapy benefit can be predicted on the basis of the pretreatment plasma cortisol and the subsequent cortisol rise. In contrast, this mechanism is likely to be beneficial in the body's response to chronic infections such as tuberculosis and could explain why anti-TNF treatment markedly increases the risk of reactivation of the disease.

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

“…These actions affect the turnover of glucocorticoids and may per se alter HPA axis function under some circumstances. Moreover, expression of 11␤-HSDs in cells involved in glucocorticoid feedback control of the HPA axis could also alter circulating hormones (179,622,624). These are endocrine effects.…”

11β-Hydroxysteroid Dehydrogenase Enzymes Modulate Effects of Glucocorticoids in Rheumatoid Arthritis Synovial Cells

“…There obviously is a need for more mouse models with cell type-specific knock-out (or overexpression) of 11βHSDs to delineate clearly the effects of each isoenzyme on glucocorticoid signaling in individual cell types and the systemic implications thereof - via paracrine or (neuro)endocrine (feedback) mechanisms [21,24]. …”

Changing glucocorticoid action: 11β-Hydroxysteroid dehydrogenase type 1 in acute and chronic inflammation

“…In rheumatoid arthritis and other inflammatory diseases however, the HPA axis appears relatively suppressed, especially given the level of systemic inflammation expected to activate the axis [4,93]. Edwards has recently hypothesised that this apparent deficiency in HPA axis activation is a result of the systemic increase in TNF-α in chronic inflammation inducing a widespread increase in 11β-HSD1 expression, including in the hypothalamus, thus amplifying negative feedback by glucocorticoids on the HPA axis [93]. Whether this is indeed the case requires experimental testing, but consistent with this hypothesis, whole body conversion of cortisone to cortisol (relative to cortisol to cortisone) is increased in patients with inflammatory disease [94] suggesting altered balance of 11β-HSD activities in favour of 11β-reductase (11β-HSD1).…”

“…If the Edwards hypothesis [93] is correct, then systemic inhibition of 11β-HSD1, particularly if administered during the night (in humans), should correct the HPA axis abnormality and boost the plasma cortisol levels. This might be enough to dampen down some of the inflammation, though 11β-HSD1 inhibition would also deprive inflamed tissues of the 11β-HSD1-mediated increase in intracellular glucocorticoid levels.…”