Reduced production of ACTH in response to chronic inflammation has been described in rheumatoid arthritis (RA) but the basis for this remains unclear. We have previously demonstrated that in RA extra-adrenal generation of cortisol is increased via upregulation of expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in inflamed tissues. This enzyme converts inactive cortisone to active cortisol. 11β-HSD1 is also expressed in the hypothalamus and pituitary where it regulates HPA axis function. We therefore hypothesised that increased central expression of 11β-HSD1 during chronic inflammation could explain the decreased production of ACTH. This hypothesis was examined in the K/BxN model of chronic inflammatory arthritis.
K/BxN transgenic mice developed arthritis at 4-5 weeks of age and were sacrificed at 8 weeks. Wild Type (WT) non-arthritic littermates were used as controls. Hypothalamic and pituitary tissues were isolated along with other brain regions. Expression of 11β-HSD1, GRα, MR, and POMC was examined by quantitative RT-PCR and immunohistochemistry.
11β-HSD1, GRα and MR were expressed in the pituitary and hypothalamus. Mice with chronic inflammation showed a significantly lower expression of 11β-HSD1 and GRα mRNA in pituitary (50.5+/-9.5% less than WT, p=0.008; 51.6+/-6.8%, p=0.002 respectively). By contrast there was no difference in 11β-HSD1 and GRα expression within the hypothalamus by RT-PCR or immunohistochemistry. Levels of 11β-HSD1, GRα and MR did not differ between arthritis mice and controls at any other brain region (hippocampus, cortex, cerebellum). Despite lower 11β-HSD1 and GRα expression (and thus lower glucocorticoid negative feedback), pituitary POMC/ACTH mRNA levels were significantly lower in arthritic mice than WT (36.5+/-4.7%, p=0.03).
Rather than being increased, 11β-HSD1 expression in the pituitary gland was suppressed. Despite this the expression of ACTH was low in keeping with reduced activity of the HPA axis. These data indicate that failure of HPA axis activation in chronic arthritis is not due to increased central 11β-HSD1 expression.