Mesenchymal stem cells prevent restraint stress-induced lymphocyte depletion via interleukin-4

Chronic stress has dramatic impacts on the immune system and consequently contributes to the onset and progression of a variety of diseases, including cancer, immune disorders, and infections. Recent studies in animals and humans have demonstrated that mesenchymal stem cells (MSCs) significantly modulate the immune system. Here we show that administration of MSCs in vivo prevents lymphocyte depletion induced by physical restraint stress (12:12-h stress-rest, 2 repetitions) in mice. This effect was found to be exerted not through modulation of glucocorticoid levels in the circulation, but rather through direct effects on lymphocyte apoptosis. By testing various possible protective mechanisms, we found that IL-4 provides a strong anti-apoptosis signal to lymphocytes in the presence of dexamethasone. When neutralizing antibody against IL-4 was co-administered with MSCs to restraint-stressed mice, the protective effect of MSCs was diminished. Furthermore, in mice deficient in STAT6, a key molecule in IL-4 receptor-mediated signaling, MSCs had no effect on restraint stress-induced lymphocyte depletion. Additionally, MSCs administered to stressed mice promoted IL-4 production by splenocytes. This study reveals that MSCs can effectively prevent stress-induced lymphocyte apoptosis in an IL-4-dependent manner and provides novel information for the development of countermeasures against the deleterious effects of stress on the immune system.