DescriptionSuperantigens (SAgs) activate the immune system by stimulating excessive proliferation of T cells, resulting in the release of cytokines such as tumor necrosis factor-alpha (TNFα). As an adaptive feedback mechanism, SAgs can also activate the hypothalamic pituitary adrenal (HPA) axis by stimulating the release of corticotropin releasing hormone (CRH) from the hypothalamus, adrenocorticotropic hormone (ACTH) from the anterior pituitary, and ultimately corticosterone (CORT) from the adrenal gland. Behavioral consequences of SAg activation include increased gustatory neophobia, neophobia to inanimate non-gustatory objects, and heightened anxiety. Cytokines such as TNFα have been shown to mediate some of these behavioral consequences as well as the endocrine and neurobiological effects of SAg exposure.
The present experiments were designed to determine the role of TNF receptor I (TNFRI) and TNF receptor II (TNFRII) in mediating the effects of acute and repeated SEA. First, the in vivo repercussions of repeated stimulation with SEA were assessed. Then TNFRI- and TNFRII-deficient animals were tested several hours after acute and secondary exposure to SEA, as well as several days after acute SEA exposure. These studies showed that TNFRI was important in mediating the anorexia and CORT response following acute SEA exposure, but not the increase in neophobia several days following exposure. In addition, TNFRI was also important in mediating the endocrine effects of repeated SEA.
Since TNFα was shown to regulate the endocrine effects of SEA, a set of experiments also confirmed that glucocorticoids play an important role in regulating TNFα tolerance following secondary SEA exposure. In addition, the consequences of glucocorticoid disruption on the effects of acute and repeated challenge with SEA were determined through the use of chronic restraint. The results showed that chronic restraint produced an overall increase in interleukin-10 (IL-10) and a blunted interleukin-2 (IL-2) response following immediate acute SEA exposure. However, when the acute exposure was given more distal to the end of restraint period there was an enhanced IL-2 and TNFα response following acute, but not secondary SEA exposure. Collectively, these studies demonstrate the reciprocal effect of TNFα and glucocorticoids after acute and repeated SEA exposure.