The role of IL17 in systemic inflammation mediated downregulation of the endothelial anti-inflammatory factor Del-1 in the adrenal gland and related HPA axis dysregulation

Adrenal gland dysfunction and hypothalamus-pituitary-adrenal (HPA) axis dissociation are common problems in patients with sepsis. Previously, we demonstrated that endothelial dysfunction may actively participate in inflammation-related adrenal insufficiency. We focused on developmental endothelial locus-1 (Del-1), an endothelial-derived anti-inflammatory factor; because we found that its expression is strongly downregulated upon systemic inflammation in the adrenal gland. Interestingly, we found that during Systemic Inflammatory Response Syndrome (SIRS), Del-1 deficiency resulted in an elevated inflammation, leukocyte accumulation and higher apoptosis in the adrenal glands, which was associated with decreased corticosterone and adrenocorticotropic hormone levels 24h post LPS-administration. These data indicated that Del-1 acts as a gatekeeper of adrenal gland inflammation and thereby of adrenal function in the course of SIRS. However, the mechanisms involved in the LPS-mediated downregulation of Del-1 in the adrenal gland remain unknown. Here we showed that interleukin-17A (IL-17A) specifically downregulate endothelial Del-1 expression. Interestingly, we found that both IL-17A and its receptor IL-17RA are induced in the adrenal gland in the course of SIRS. Along the same line, IL-17RA-deficient mice displayed increased corticosterone but not ACTH secretion during LPS-mediated SIRS. We currently pursue the hypothesis that the IL-17/IL-17R axis is a negative regulator in adrenal dysfunction by downregulating Del-1 and promoting adrenal inflammation.