Endocrine Abstracts

The neonatal immune system is not fully developed, making neonates more susceptible to early-life infection. Early-life activation of the immune system has lasting implications for health and disease. Glucocorticoids (GCs) are steroid hormones that modulate the immune response and increase in response to immune activation. GCs are produced by the adrenal glands and also by lymphoid organs (e.g., bone marrow, thymus, spleen). In neonatal mice, GC levels increase acutely in blood and lymphoid organs in response to the endotoxin, lipopolysaccharide (LPS, derived from E. coli). Yet, it is not known how early-life LPS exposure affects lymphoid organ GC levels in adulthood. We assessed whether LPS administration during the neonatal period (‘first hit’) in mice affects GC regulation in blood and lymphoid organs in adulthood when challenged again with LPS (‘second hit’). We administered LPS (50 μg/kg i.p.) or saline (vehicle control) to male and female C57BL/6J neonatal mice at post-natal day (PND) 4 and 6. We further split the mice into two groups and administered LPS (50 μg/kg i.p.) or saline in adulthood (PND90) (2x2 design). 4 hr after LPS administration at PND90, we collected whole blood, bone marrow, thymus, and spleen. We bisected the tissues and measured a panel of 10 steroids via liquid chromatography tandem mass spectrometry (LC-MS/MS) and transcripts of key steroidogenic enzymes (Cyp11b1, Hsd11b1, Hsd11b2), GC receptor (GR), and mineralocorticoid receptor (MR) via RT-qPCR. Neonatal LPS treatment altered LPS-stimulated, but not baseline, GC levels in adult mice. Specifically, neonatal LPS treatment increased lymphoid, but not blood, levels of corticosterone (main active GC in mice) and 11-dehydrocorticosterone (corticosterone metabolite) in LPS-treated males, but not females. Transcripts of key steroidogenic enzymes were present in all lymphoid organs, and there were effects of neonatal treatment in LPS-treated adults for some transcripts. Transcripts of GR and MR were present in all lymphoid organs, and neonatal LPS treatment decreased GR and MR transcript levels in the spleen of LPS-treated males and females. These results suggest that LPS exposure during early life has long-term effects on GC signaling in lymphoid organs. Importantly, these data demonstrate that lymphoid organs modulate local GC levels independently of circulating GC levels. Local GC production is a potential mechanism by which early-life bacterial infections can exert long-lasting programming effects on the immune system.