Chronic restraint stress promotes lymphocyte apoptosis by modulating CD95 expression

Depending on the duration and severity, psychological tension and physical stress can enhance or suppress the immune system in both humans and animals . Although it is well established that stress alters the release of various hormones and neurotransmitters, the mechanisms by which stress affects imm une responses remain elusive. We report here that mice subjected to chronic 12-hour daily physical restraint for two days exhibited a significant redu ction in splenocytes, a process likely mediated by apoptosis as demonstrate d by the terminal deoxynucleotidyl transferase-mediated deoxyuridine tripho sphate nick end labeling assay. CD95 (Fas/APO-1) expression in splenic lymp hocytes of stressed mice was substantially increased. Interestingly, Fas-im munoglobulin fusion protein and blocking antibodies against CD95 ligand inh ibit stress-induced reduction in lymphocytes. The stress-induced changes in CD95 expression and lymphocyte number could be blocked by naltrexone or na loxone, specific opioid receptor antagonists, indicating a pivotal role of endogenous opioids in this process. In addition, the reduction of splenocyt es in this model system seems to be independent of the hypothalamo-pituitar y-adrenal axis, as both adrenalectomized and sham-operated mice exhibited s imilar responses to chronic stress. Moreover, chronic physical restraint fa iled to induce a decrease in lymphocyte numbers in CD95-deficient (Fas(lpr/ lpr)) mice. Therefore, stress modulates the immune system through CD95-medi ated apoptosis dependent on endogenous opioids.