Fig. 3.

Mechanism for attenuated febrile responses in neonatally LPS-treated animals. A: in animals not treated with LPS as neonates, i.e., in the normal innate immune response, LPS acts on TLR4 on immune cells. An immune cascade is initiated whereby COX-2 is activated in liver macrophages (Kupffer cells and possibly other immune cells elsewhere), promoting PG (e.g., PGE₂) release into the circulation to signal to the brain, contributing to the onset of fever. At the level of the immune cell, NF-κB also triggers synthesis and release of proinflammatory cytokines (e.g., TNFαand IL-1β or -6), which activate the brain, stimulating COX-2 to catalyze further production of PGE₂. In addition to contributing to the onset of fever, PG cause an initial ACTH release from the anterior pituitary and glucocorticoid release from the adrenal cortex. Glucocorticoids have anti-inflammatory actions to limit peripheral cytokine synthesis. B: in animals treated with LPS as neonates, there is a constitutive upregulation of TLR4 on immune cells in the spleen and liver as well as constitutive upregulation of COX-2. In these animals, adult LPS causes a rapid enhanced rise in plasma PGE₂ that results in an early glucocorticoid surge that acts on the immune cells to suppress cytokine production, thereby resulting in a reduced febrile response.