Glucocorticoid Production in Lymphoid Organs: Acute Effects of Lipopolysaccharide in Neonatal and Adult Mice

Abstract

Glucocorticoids (GCs) are critical modulators of the immune system. The hypothalamic-pituitary-adrenal (HPA) axis regulates circulating GC levels and is stimulated by endotoxins. Lymphoid organs also produce GCs; however, it is not known how lymphoid GC levels are regulated in response to endotoxins. We assessed whether an acute challenge of lipopolysaccharide (LPS) increases lymphoid levels of GCs, steroidogenic enzymes expression, and components of the HPA axis (e.g., CRH) expression. We administered LPS (50µg/kg i.p.) or vehicle control to male and female C57BL/6J neonatal (post-natal day (PND) 5) and adult (PND90) mice and collected blood, bone marrow, thymus, and spleen 4 hr later. We measured progesterone, 11-deoxycorticosterone (DOC), corticosterone, and 11-dehydrocorticosterone (DHC) via liquid chromatography tandem mass spectrometry (LC-MS/MS). We measured gene expression of key steroidogenic enzymes (Cyp11b1, Hsd11b1, and Hsd11b2) and HPA axis components (Crh, Crhr1, Pomc, and Mc2r) via qPCR. At PND5, LPS induced greater increases in steroid levels in lymphoid organs than in blood. In contrast, at PND90, LPS induced greater increases in steroid levels in blood than in lymphoid organs. Steroidogenic enzyme transcripts were present in all lymphoid organs, and LPS altered steroidogenic enzyme expression predominately in the spleen. Lastly, we detected transcripts of key HPA axis components in all lymphoid organs, and there was an effect of LPS in the spleen. Taken together, these data suggest that LPS regulates GC production by lymphoid organs, similar to its effects on the adrenal glands, and the effects of LPS might be mediated by local expression of CRH and ACTH.

Environmental Enrichment Protects Against Sepsis-Associated Encephalopathy-Induced Learning and Memory Deficits by Enhancing the Synthesis and Release of Vasopressin in the Supraoptic Nucleus

“…Endotoxins can stimulate the hypothalamic–pituitary–adrenal (HPA) axis and the ensuing hippocampal circuit is triggered. 92 Therefore, we cannot rule out the influence of infection itself.…”

Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth

“…In kidney and colon cells, these active glucocorticoids are metabolized (inactivated) by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2, encoded by Hsd11b2), producing cortisone (human) or dehydrocorticosterone (mouse). These inactive species are present at high levels in the blood (7,8) and can be converted back to their active counterparts by 11β-HSD1 (11β-hydroxysteroid dehydrogenase type 1, encoded by Hsd11b1), providing a mechanism of glucocorticoid generation distinct from de novo synthesis. 11β-HSD1 expression is highest in the liver, but it is also expressed in many other tissues, including adipose tissues, brain, and lymphoid organs (9,10).…”