Long term alterations in neuroimmune responses of female rats after neonatal exposure to lipopolysaccharide

Abstract

Male and female rats display significant gender-associated differences in their responses to an immune challenge, and gender-specific alterations in many aspects of physiology are seen after a variety of interventions during the neonatal period. It is well-established that neonatal exposure to an immune challenge can alter centrally mediated inflammatory responses in adult male rats and yet little is known about female responses after a similar challenge. We therefore asked if neonatal exposure to lipopolysaccharide (LPS) would alter febrile and hypothalamic cyclooxygenase (COX)-2 responses to an adult immune challenge in female rats. Female Sprague–Dawley rats were administered a single injection of the bacterial endotoxin LPS at postnatal day 14 and were examined as adults for febrile, COX-2 and activity changes to LPS, as well as responses to interleukin (IL)-1β. Adult female rat responses were similar to those we have seen previously for the males in that febrile and hypothalamic COX-2 responses to adult LPS were attenuated in neonatally LPS-treated animals. Responses to adult IL-1β were unaffected. Interestingly, females did not display the elevated basal hypothalamic COX-2 that was previously seen in males. Thus we demonstrate that, like in the males, neonatal exposure to LPS has a powerful effect on adult responses to further LPS challenge in the female rats.

Introduction

Exposure to an infection or an immune stimulant such as lipopolysaccharide (LPS) induces synthesis of pro-inflammatory cytokines, for example interleukin (IL)-1β and IL-6, causing an acute-phase response of which one component is fever. This febrile response is an integral part of the host defense against the invasion of pathogens, and is associated with an increased ability to combat infection and increased survival (Blatteis et al., 2000).

It is well established, however, that there are significant gender related differences, in humans and other mammals in the response to an immune challenge and that the sex hormones progesterone and estrogen are important in these differential responses (Martin, 2000). It is known that female rodents display greater hypothalamic–pituitary–adrenal (HPA) axis responses to immune challenge (Watanobe and Yoneda, 2003). Females have higher peak basal corticosterone levels as well as greater increases in corticosterone and adrenocorticotropic hormone (ACTH) in response to LPS compared with male rats (Critchlow et al., 1963, Seale et al., 2004, Watanobe and Yoneda, 2003). Female rats also display a significantly lower second phase febrile response to intraperitoneal (i.p.) LPS (Taylor et al., 2005), a reduction most likely due to estrogen and progesterone (Mouihate and Pittman, 2003).

It is particularly interesting that a variety of interventions and perturbations during the neonatal period, including maternal separation, neonatal handling, and immune challenge result in gender specific alterations in the adult (Barr et al., 2004, McCormick et al., 1995, Papaioannou et al., 2002, Park et al., 2003, Smythe et al., 1994, Weinberg et al., 1978). We have previously reported that male rats exposed as neonates at postnatal day (P)14 to LPS have elevated basal hypothalamic cyclooxygenase (COX)-2 levels, as well as attenuated febrile and COX-2 responses to a further dose of LPS in adulthood (Boissé et al., 2004, Ellis et al., 2005), while the response to LPS eight weeks after adult LPS pre-treatment is not affected (Boissé et al., 2004). Thus, neonatal exposure to an immune challenge, in the form of LPS, can alter centrally mediated inflammatory responses in adult male rats.

Given the differences in the innate immune responses of males and females, we therefore wanted to determine whether neonatal exposure to LPS alters adult COX-2 and febrile responses in female rats in a similar manner to that previously observed in the males. Thus, P14 female rats were administered an i.p. injection of either pyrogen-free saline (controls), Escherichia coli LPS, or Salmonella enteritidis LPS. Once these rats reached adulthood they were assessed for temperature, activity and COX-2 responses to a further injection of LPS to test whether neonatal exposure to an immune challenge also alters febrile and neurochemical responses to LPS in adult females.