Pro-inflammatory cytokines activate the hypothalamic pituitary adrenal (HPA) axis but chronic inflammatory diseases such as Rheumatoid Arthritis (RA) do not. The axis is subtly subnormal despite nocturnal cytokine peaks. This poses the question Why does the endocrine dog not bark in the cytokine night?. Is this chronic stress adaptation similar to that seen with restraint when the normotypic stressor is reduced with decreased parvocellular CRH mRNA, a compensatory increase in AVP and enhanced response to a heterotypic stress. However this latter response does not occur in chronic inflammatory stress such as adjuvant arthritis. Chronic inflammation is associated with increased conversion of inactive cortisone to cortisol by 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) which is markedly increased by pro-inflammatory cytokines such as TNF. This is an important autocrine mechanism at the inflammatory site. However the systemic effects may amplify inflammation by altering the cortisol circadian rhythm (lower nadir, delayed morning rise, impaired stress response), decreasing cortisol production rate and producing relative adrenal atrophy. If this hypothesis is correct then there is a nocturnal window of glucocorticoid insufficiency. This could explain: 1) Why low dose prednisolone given to RA patients at 0200 h is so much more effective than at 0730 h. 2) Why chronic inflammatory diseases are associated with low adrenal androgens. 3) Why anti-TNF therapy activates the HPA axis and increases adrenal androgens. 4) Why the beneficial effects of anti-TNF can be predicted on pre-treatment basal cortisol and its subsequent rise. 5) Why 11β-HSD inhibitors prevent adjuvant arthritis in animal models and are effective in its treatment. 6) Why anti-TNF reactivates TB. Animal models of TB indicate major evolutionary advantages for the endocrine dog not barking in the cytokine night. Modern man with non-infectious chronic inflammatory disease is less fortunate.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.