Fever is the most common manifestation of the innate immune response to invading pathogens. Animals prevented from developing fever have increased morbidity and mortality to infection. We now show that early life events can program this innate immune response, in that rats that have been challenged neonatally with the immune stimulant lipopolysaccharide (LPS) have both suppressed febrile responses to LPS as adults and significantly reduced nuclear factor (NF)-kappaB activation in peripheral immune organs. This was associated with reduced levels of proinflammatory cytokines tumor necrosis factor (TNF)-alpha, and interleukin-6 (IL-6) in the plasma after adult LPS challenge, compared with animals that have received saline neonatally. In contrast, adult LPS challenge elicited higher corticosterone levels in the animals that had been treated neonatally with LPS. When this increased corticosterone response was negated by adrenalectomy or by administration of the glucocorticoid receptor antagonist RU-486, both the cytokine and febrile responses were normalized. This study indicates that the innate immune response can be programmed by a neonatal LPS challenge, whereby an amplified hypothalamic-pituitary-adrenal response causes reduced cytokine synthesis and an attenuated febrile response to an adult immune challenge. In light of the importance of fever in the host defense response, these alterations may have deleterious consequences on an individual's ability to combat disease later in life.

Fever is an integral part of the host's defense to infection that is orchestrated by the brain. A reduced febrile response is associated with reduced survival. Consequently, we have asked if early life immune exposure will alter febrile and neurochemical responses to immune stress in adulthood. Fourteen-day-old neonatal male rats were given Escherichia coli lipopolysaccharide (LPS) that caused either fever or hypothermia depending on ambient temperature. Control rats were given pyrogen-free saline. Regardless of the presence of neonatal fever, adult animals that had been neonatally exposed to LPS displayed attenuated fevers in response to intraperitoneal LPS but unaltered responses to intraperitoneal interleukin 1␤ or intracerebroventricular prostaglandin E 2 . The characteristic reduction in activity that accompanies fever was unaltered, however, as a function of neonatal LPS exposure. Treatment of neonates with an antigenically dissimilar LPS (Salmonella enteritidis) was equally effective in reducing adult responses to E. coli LPS, indicating an alteration in the innate immune response. In adults treated as neonates with LPS, basal levels of hypothalamic cyclooxygenase 2 (COX-2), determined by semiquantitative Western blot analysis, were significantly elevated compared with controls. In addition, whereas adult controls responded to LPS with the expected induction of COX-2, adults pretreated neonatally with LPS responded to LPS with a reduction in COX-2. Thus, neonatal LPS can alter CNS-mediated inflammatory responses in adult rats.

A single postnatal exposure to the bacterial endotoxin, lipopolysaccharide (LPS), reduces the neuroimmune response to a subsequent LPS exposure in the adult rat. The attenuated fever and proinflammatory response is caused by a paradoxical, amplified, early corticosterone response to LPS. Here we identify the mechanisms underlying the heightened corticosterone response to LPS in adults after early life exposure to LPS. In postnatal LPS-treated rats, hypothalamic corticotrophin-releasing hormone mRNA, pituitary proopiomelanocortin mRNA, and circulating adrenocorticotrophic hormone were all increased after adult exposure to LPS without significant modification to hippocampal or hypothalamic glucocorticoid receptor mRNA or protein or vagally mediated afferent signaling to the brain. Postnatal LPS administration did cause a persistent upregulation of the LPS Toll-like receptor-4 (TLR4) mRNA in liver and spleen, but not in brain, pituitary, or adrenal gland. In addition, cyclooxygenase-2 (COX-2), which is a prostaglandin biosynthetic enzyme and is normally undetectable in most peripheral tissue, was constitutively expressed in the liver. Adult immune activation of the upregulated TLR4 and COX-2 caused a rapid, amplified rise in circulating, but not brain, prostaglandin E 2 that induced an early, enhanced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Thus, postnatal LPS reprograms the neuroimmune axis by priming peripheral tissues to create a novel, prostaglandin-mediated activation of the HPA axis brought about by increased constitutive expression of TLR4 and COX-2.

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pregnant rats show a suppressed fever response to LPS that is associated with reduced induction of cyclooxygenase (COX)-2 in the hypothalamus. The objective of this study is to explore whether the LPS-activated signaling pathways in the fever-controlling region of the hypothalamus are specifically altered at near term. Three rat groups consisting of 15-day pregnant rats, near-term 21-to 22-day pregnant rats, and day 5 lactating rats were injected with a febrile dose of LPS (50 g/kg ip). The hypothalamic preoptic area and the organum vasculosum of the lamina terminalis (OVLT) were collected 2 h after LPS injection. The activation of three transcription modulators, nuclear factor-B (NF-B), extracellular signal-regulated kinase 1/2 (ERK1/2), and signal transducer and activator of transcription 5 (STAT5), was assessed using semiquantitative Western blot analysis. LPS activated the NF-B pathway in all rat groups, and this response was not altered at near term. ERK1/2 and STAT5 were constitutively activated during all reproductive stages, and their levels were not significantly affected by LPS injection. Plasma levels of the proinflammatory cytokines (IL-1␤, IL-6, TNF-␣, and IFN-␥), anti-inflammatory cytokines (IL-4, IL-10, and IL-1 receptor antagonist), and corticosterone were unaffected during the three reproductive stages after LPS challenge. We observed a sharp decrease in the expression of a prostaglandinproducing enzyme called lipocalin-prostaglandin D 2 synthase in nearterm pregnant and lactating rats. Thus fever suppression at near term is not due to an alteration in either LPS-activated intracellular signaling pathways or LPS-induced pro-and anti-inflammatory cytokine production.reproduction; cytokine; nuclear factor-B; extracellular signal-regulated kinase 1/2; signal transducer and activator of transcription 5