Neuronal, Endocrine, and Anorexic Responses to the T-Cell Superantigen Staphylococcal Enterotoxin A: Dependence on Tumor Necrosis Factor-α

Abstract

Staphylococcal enterotoxin A (SEA) is a microbial superantigen that activates T-lymphocytes and induces production of various cytokines, including tumor necrosis factor-␣ (TNF␣). Previously, it was shown that SEA activates the hypothalamic-pituitary-adrenal axis and augments gustatory neophobic behaviors. In the present study, it was hypothesized that these effects involve neuronal activation in forebrain regions mediating fear and/or anxiety and are dependent on the production of TNF␣. Male C57BL/6J mice were given intraperitoneal injections of 10 g of SEA and 5 g of lipopolysaccharide (LPS) or saline and perfused 2 h later for histochemical determination of brain c-Fos immunoreactivity (IR). The results showed increased c-Fos IR in the paraventricular nucleus, arcuate nucleus, central nucleus of the amygdala, bed nucleus of the stria terminalis, and lateral septum. Challenge of TNF Ϫ/Ϫ mice with SEA did not produce a significant increase in brain c-Fos IR, although c-Fos was increased after exposure to a psychogenic stressor (i.e., open field). In additional experiments, the elevated corticosterone response to SEA was abrogated in TNF Ϫ/Ϫ mice and was shown to be corticotropin-releasing hormone dependent. Finally, the augmented reduction in novel food intake after SEA challenge was attenuated in TNF Ϫ/Ϫ mice as well as in wild-type mice administered antibody to TNF␣. In conclusion, challenge with SEA recruits brain regions mediating stress and anxiety responses, an effect that requires endogenous TNF␣. Whether this is indicative of all T-cell superantigens remains to be determined, although it stands in contrast to other models of neuroimmunomodulation (e.g., LPS) that involve multiple cytokine influences.

Methylmercuric chloride induces activation of neuronal stress circuitry and alters exploratory behavior in the mouse

“…Brains were sectioned at 30μm on a Leica SM 2000R freezing microtome and stored in cryoprotectant until assayed. Immunohistochemical detection of cFos was conducted using a free-floating assay as described previously (Rossi-George et al, 2005). Cryopreserved sections were washed with KPBS, incubated with rabbit anti-mouse, anti-Fos primary antibody (1:15,000) (CalBiochem, La Jolla, CA) for 2h at room temperature, and then at 4°C for 48h.…”

“…Images were taken on a Nikon Eclipse E400 microscope with 10−20× objectives. Fos-positive cells were counted with NIH Scion Image software as previously described (Rossi-George et al, 2005). The quantification of c-Fos positive cells was conducted on coded slides thereby rendering the experimenter blind to all treatments.…”

“…In recent years, a distinction has been made between psychogenic stressors, that engage neural circuitry by way of initial information processing (hence, processive stressors), and systemic stressors, which impact the brain as a function of internal physiological changes (e.g., metabolic challenges and immune responses) (Herman & Cullinan, 1997;Rossi-George et al, 2005). Sustained, chronic exposure to psychogenic stressors has been the basis of theories of adaptational breakdown that may lead to psychiatric conditions, such as anxiety and depression (McEwen, 2004).…”

“…Sustained, chronic exposure to psychogenic stressors has been the basis of theories of adaptational breakdown that may lead to psychiatric conditions, such as anxiety and depression (McEwen, 2004). Behavioral experimentation has also demonstrated that modulation of T-cell immune responses occurs in response to neuroendocrine activation following chronic stress (Silberman et al, 2003, Reichlin 2004, Kusnecov & Goldfarb, 2005. Psychological stressors have also been shown to deleteriously affect the immune response to bacterial infection and progression of autoimmune neurodegenerative diseases such as multiple sclerosis Kiank et al, 2006).…”

“…Lipopolysaccharide exposure has also been demonstrated to increase permeability of the bloodbrain barrier, increase lymphocyte proliferation, and activation of stress-associated brain circuits (Jaworowicz et al, 1998;Ulmer et al, 2000;Lenczowski et al, 1998). Further, LPS is also a well known activator of cFos production within the murine brain (Akasaka et al, 2006;Brochu et al, 1999,Rossi-George et al, 2005. To date however there is little information addressing how repeated treatment of MeHg affects cFos expression within the brain's stress circuitry, and in addition, influences subsequent responses to bacterial endotoxin.…”