Endocrine Abstracts

The anti-inflammatory protein, annexin 1 (ANXA1) acts via a formyl peptide receptor (FPR), possibly FPR2, in the neuroendocrine system to mediate feedback effects of glucocorticoids and thereby modulate the HPA responses to immune insults. Here, we explored further the role of ANXA1 and the FPR family in mediating the HPA responses to endotoxin (LPS), focusing on the adrenal cortex.

Adult male mice treated with LPS (500 μg/kg, i.p.) showed time-dependent increases in murine ANXA1 (mANXA1), mFPR1, mFPR2 and mFPR3 mRNAs in the pituitary, adrenal gland and spleen (positive control), but not in the hippocampus or hypothalamus. There were also increases in corticosterone, pro-inflammatory cytokines and at 4 h (peak upregulation) in the adrenal cortex, inflammatory cell infiltration (predominantly eosinophils) and reduced vacuolation in the steroidogenic cells were seen. In vitro, adrenal cells from LPS-treated mice were given ACTH (0.1–10 μM) but failed to release corticosterone, unlike saline treated mice. The LPS-induced inflammatory cell infiltration was unaffected by ANXA1 or FPR2 gene deletion, but vacuolation was present, unlike their WT counterparts. In mice depleted of polymorphonuclear leukocytes (PMNs), LPS still induced increases in corticosterone and pro-inflammatory cytokines and reduced vacuolation. With inflammatory cell infiltration in the adrenal cortex absent or dramatically reduced, an upregulation of mRNA for mFPR2 only occurred (mFPR1 and mFPR3 unaffected) in LPS treated mice. As before the N-terminal ANXA1 peptide (ANXA1_Ac2–26, 10–30 μM) inhibited ACTH-induced corticosterone release in vitro from adrenal cells from control mice; its effects were mimicked by high (1.0–10 μM) but not low (0.1 μM) concentrations of formyl peptide (fMLP), suggesting ANXA1 effects may be mediated via FPR2.

These data raise the possibility that adrenal function may be compromised in endotoxaemia both through impaired steroidogenesis, due to substrate depletion, and the cytotoxic actions of infiltrating inflammatory cells. The roles of ANXA1 and FPR2 in modulating steroidogenesis require further investigation, along with the unexplored roles of FPR1 and FPR3 in the adrenal cortex.