Effect of Repeated Lipopolysaccharide Administration on Tissue Cytokine Expression and Hypothalamic−Pituitary−Adrenal Axis Activity in Rats

The effects of chronic immune challenge on cytokine expression and hypothalamic−pituitary−adrenal axis (HPA) axis responses to stress were studied in Wistar rats after administration of increasing doses of lipopolysaccharide (LPS). Repeated LPS (R−LPS) decreased body weight and increased adrenal weight and pituitary pro−opiomelanocortin mRNA levels. LPS injection increased plasma adrenocorticotropic hormone (ACTH) and corticosterone but the effect was attenuated in R−LPS. Plasma corticosterone but not ACTH responses to restraint were also reduced in R−LPS. Basal and restraint−stimulated corticotropin releasing hormone (CRH) mRNA levels were lower in R−LPS, but responses to a new LPS injection were similar to controls. In contrast, type 1 CRH receptor (CRH−R1) mRNA responses to both LPS and restraint were blunted in R−LPS. Vasopressin mRNA levels in parvocellular neurones were higher in R−LPS, and increased further after restraint but not after a new LPS injection. Glucocorticoid receptor (GR) levels in the paraventricular nucleus (PVN) increased after a single LPS or R−LPS (24 h after the last injection) but declined after a new injection in R−LPS. Interleukin (IL)−1b and IL−6 mRNAs increased in the pituitary, spleen and circumventricular organs after single or R−LPS, suggesting that cytokines may contribute to the activation of the HPA axis though pathways from the circumventricular organs as well as paracrine effects in the pituitary. The data show that (i) adaptation of the HPA axis during repeated LPS injection involves increases in vasopressin :CRH expression ratios in parvocellular neurones; (ii) that hypothalamic CRH and vasopressin responses to acute stimulation are independent of CRH−R1 expression in the PVN; and (iii) there is a dissociation between pituitary and adrenal responses to acute stress suggesting a decrease of adrenal sensitivity to ACT