Chronic Restraint Stress Promotes Lymphocyte Apoptosis by Modulating Cd95 Expression

Abstract

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 immune responses remain elusive. We report here that mice subjected to chronic 12-hour daily physical restraint for two days exhibited a significant reduction in splenocytes, a process likely mediated by apoptosis as demonstrated by the terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling assay. CD95 (Fas/APO-1) expression in splenic lymphocytes of stressed mice was substantially increased. Interestingly, Fas-immunoglobulin fusion protein and blocking antibodies against CD95 ligand inhibit stress-induced reduction in lymphocytes. The stress-induced changes in CD95 expression and lymphocyte number could be blocked by naltrexone or naloxone, specific opioid receptor antagonists, indicating a pivotal role of endogenous opioids in this process. In addition, the reduction of splenocytes in this model system seems to be independent of the hypothalamo-pituitary-adrenal axis, as both adrenalectomized and sham-operated mice exhibited similar responses to chronic stress. Moreover, chronic physical restraint failed to induce a decrease in lymphocyte numbers in CD95-deficient (Faslpr/lpr) mice. Therefore, stress modulates the immune system through CD95-mediated apoptosis dependent on endogenous opioids.

Osteopontin: Role in immune regulation and stress responses

“…Furthermore, endogenous opioids are known to be elevated by stress and to play a critical role in regulating stress-induced changes in the immune system (Kowalski, 1998). Opioid receptor antagonists Naltrexone and Naloxone also suppressed stress-induced reduction of splenocytes (Yin et al, 2000). The studies presented in this dissertation showed that OPN deficiency caused the same effects as these antagonists.…”

“…It has been well documented that mice subjected to chronic physical stress exhibit an increased rate of lymphocyte apoptosis, redistribution of immune cells to the periphery and atrophy in the thymus and the spleen (Yin et al, 2000;Offner et al, 2006). Based on these observations, lymphoid organ atrophy is a convenient marker for monitoring stress-induced changes in the immune system.…”

“…The opioid receptor antagonists Naltrexone and Naloxone also suppress stress-induced reduction in splenocyte number (Yin et al, 2000). OPN deficiency seems to resemble the effects of these hormone antagonists, suggesting a connection between OPN and the HPA axis.…”

“…Eight to ten-week-old mice were subject to an established CRS protocol with some modification (Yin et al, 2000). OPN +/+ and OPN -/-mice were each divided into control and stress groups.…”

“…To verify the involvement of OPN in the stress response revealed in the HU model, I used a well established chronic stress model (CRS) (Yin et al, 2000) to evaluate OPN -/-mice. To reduce the possibility that differences in genetic background could affect the response to stress, OPN-deficient mice under Balb/c background were tested in parallel with 129 mice.…”