Comparing two anti-inflammatory reflexes: Splanchnic and hypothalamic–pituitary–adrenal

Both the autonomic nervous system and the hypothalamic-pituitary-adrenal axis respond to systemic immune challenge by initiating anti-inflammatory reflexes. Here we compare those two homeostatic responses in vivo. We first confirmed in male urethane-anaesthetized rats that disabling the autonomic reflex by bilateral section of the splanchnic sympathetic nerves increased plasma tumor necrosis factor α (TNF) responses to systemic lipopolysaccharide (LPS, 60 µg/kg i.v.) while reducing levels of the key anti-inflammatory cytokine, interleukin 10 (IL-10). Bilateral adrenalectomy, removing both adrenal catecholamines and glucocorticoids, increased TNF responses to LPS by a factor similar to splanchnic nerve section, but unlike splanchnic nerve section, did not reduce IL-10 responses. Both the splanchnic anti-inflammatory reflex and the adrenal glucocorticoid response independently suppress TNF production. When either pathway was disabled individually, TNF responses to LPS increased. When both were disabled simultaneously, by combining adrenalectomy with splanchnic nerve section, TNF levels rose further, in an approximately additive manner. In contrast, IL-10 responses reflected the balance between catecholamine-driven enhancement and glucocorticoid-mediated suppression. When compared to adrenal nerve section, which prevents adrenal catecholamine release, bilateral adrenalectomy (removing both adrenaline and glucocorticoids) actually increased IL-10 responses to LPS. This indicates that circulating glucocorticoids actively suppress IL-10 as well as TNF. That inference was confirmed by restoring plasma corticosterone levels in adrenalectomized rats. We conclude that systemic immune challenge initiates two early, powerful anti-inflammatory reflexes that suppress TNF with similar potency. These reflexes act through independent mechanisms and exert opposing control over IL-10, highlighting their broader regulatory role in cytokine balance.