Physical defeat reduces the sensitivity of murine splenocytes to the suppressive effects of corticosterone
Introduction
Stressors alter immune functioning in most organisms and often enhance their susceptibility to infectious diseases. Experimental models of social stress in rodents, typically involving confrontations between conspecifics, have been widely used to illustrate the effects of these stressors on immunity (Stefanski, 2001). These stress-effects can be either immunostimulatory or immunosuppressive depending on the nature of the stressor and the specific immunological measure. For example, phagocytic activity of peritoneal macrophages is known to be enhanced in mice exposed to a brief social conflict paradigm (Lyte et al., 1990). On the other hand, other measures of immunity, such as mitogen-induced lymphocyte proliferation, cytokine production, or antibody production may be enhanced, suppressed, or unchanged depending on the experimental conditions (Bohus et al., 1993; de Groot et al., 1999; Fleshner et al., 1989).
Stressor-induced immunomodulation is the result of interactions with many different stress-responsive neuroendocrine systems, however interactions with the sympathetic nervous system (SNS) and the hypothalamic–pituitary–adrenal (HPA) axis are by far the most well studied. Many immune cells, including lymphocytes (Fuchs et al., 1988; Landmann, 1992), monocytes (Abrass et al., 1985; Fuchs et al., 1988; Maisel et al., 1990), and granulocytes (Galant et al., 1978; Maisel et al., 1990) express functional adrenergic and glucocorticoid (McEwen et al., 1997) receptors that exert a variety of biological functions when bound to their ligands. These neuroendocrine-induced effects on the immune system are often believed to be adverse side effects that ultimately have negative impacts on overall health. However, the nervous system may play a more direct role in regulating the immune response, and may be necessary to enhance host defenses in some situations. For example, during influenza-A infection, lung cellularity and excessive inflammation was significantly decreased in restrained mice. Interestingly, this protective effect could be blocked with the glucocorticoid receptor antagonist RU486, thus demonstrating the important regulatory role that corticosterone has in mediating inflammation (Hermann et al., 1995; Sheridan et al., 2000). In contrast to restraint, social reorganization, a social stressor in mice, resulted in increased lung cellularity and mortality from lung consolidation after influenza-A infection, even though the infection resulted in significantly elevated concentrations of corticosterone (Sheridan et al., 2000). This study led to the hypothesis that social stressors reduce the sensitivity of murine leukocytes to the suppressive effects of corticosterone.
Several studies have supported the hypothesis that social stressors affect steroid sensitivity in mice. For example, enhanced cell survival of lipopolysaccharide (LPS)-stimulated splenocytes after 48 h in culture in the presence of physiological (0.005 μM) or even pharmacological doses of corticosterone (5 μM) is evident after exposure to the social disruption (SDR) paradigm or paired fighting (Avitsur et al., 2001, Avitsur et al., 2002a, Avitsur et al., 2002b; Quan et al., 2001, Quan et al., 2003; Stark et al., 2001, Stark et al., 2002). This effect is more likely to develop in defeated mice, and is associated with bite wounds that occur during the aggressive interactions (Avitsur et al., 2002b). Although this seems to suggest that wounding alone reduces splenocyte sensitivity to corticosterone, artificial wounds (full thickness skin biopsies) are not sufficient to induce this phenomenon (Avitsur & Sheridan, unpublished observations), further placing emphasis on the role of the aggressive interactions in reducing corticosterone sensitivity. These aggressive interactions have at least two components, the physical attack (which would include wounding) and the threat of attack (also called psychosocial stimulation) (Martinez et al., 1998; Sgoifo et al., 1998). Because these two characteristics may be intimately linked in the SDR paradigm (i.e., animals that are attacked more often may have increased psychosocial stimulation), it has been difficult to determine whether the psychological, physical, or both components of the aggressive interactions are necessary to affect splenocyte sensitivity to glucocorticoids. Therefore, the current study was conducted to determine whether the physical act of being attacked and defeated or the associated psychosocial stimulation would enhance LPS-stimulated splenocyte viability in the presence of physiological and pharmacological doses of corticosterone.
Section snippets
Animals
Male C57BL/6 mice between the ages of 6–8 weeks were purchased from Charles River (Wilmington, MA) and allowed to acclimate to the animal facility for 1 week prior to the experiment. Depending on the experimental condition, the mice were housed in groups of 3 or 5 per cage, with all mice being maintained on a 12-h light/dark schedule (lights on at 06:00). Mice had free access to food and water except during the 2-h stress period when they only had access to water. All procedures were approved by
Results
The experimental paradigm had profound effects on corticosterone levels on both days they were measured (; Fig. 2). This effect was most pronounced in the SDR Physical Contact animals that had significantly higher corticosterone levels than the Home Cage Controls (p<.05). In addition, corticosterone levels were elevated in the SDR Sensory Contact animals and the SDR No Contacts in comparison to the Home Cage Controls (p<.05), but were significantly lower than corticosterone
Discussion
This study replicates previous reports demonstrating that SDR significantly elevates corticosterone levels in vivo and renders splenocytes less sensitive to the suppressive effects of corticosterone after LPS stimulation (Avitsur et al., 2001, Avitsur et al., 2002a, Avitsur et al., 2002b; Quan et al., 2003; Stark et al., 2001, Stark et al., 2002). However, prior to this study, it was unknown whether the threat of attack alone would reduce splenocyte corticosterone sensitivity. Our data indicate
Acknowledgements
The authors gratefully acknowledge the expert technical assistance of Ms. Kari Kramer and Mr. Mark Nelson. The corticosterone assays were performed by Ms. Susan Moseley at the O.S.U. College of Medicine. Funding was provided by NIH Grant No. MH46801 to J.F.S.; M.T.B. was supported by NIDCR training Grant DE14320.
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