Interleukin 6 (IL-6) is a pleiotropic cytokine produced by the cells of immune and nonimmune origin. Increased production of IL-6 is associated with disturbances of homeostasis, such as trauma, sepsis, or inflammatory diseases. Endotoxemia, tissue injury, or immune inflammatory reactions as well as physical or psychological stress are known to cause increased production of IL-6. We have confirmed this by showing that rats exposed to electric footshock, physical restraint, or a conditioned aversive stimulus have increased levels of plasma IL-6. Interestingly, the kinetics of the increase in plasma IL-6 resembled that of increase in plasma corticosterone. As no detectable endotoxin was found in the plasma samples from stressed and nonstressed rats and there is no evidence of tissue damage and inflammation in situations of restraint or conditioned aversive stimulus, a nonimmune origin of IL-6 is possible. Thus, the releasing of IL-6 into plasma may be under the regulation of neural and endocrine responses to stress. This hypothesis is supported by the decreased production of IL-6 in cultures of splenic cells and peripheral blood mononuclear cells from stressed animals. Furthermore, substantial attenuation of increased plasma IL-6 was achieved by adrenalectomy but not by pretreatment with the beta-receptor antagonist propranolol. The important role of the adrenal gland in the IL-6 response to stress suggests that increased plasma IL-6 may be part of the hormonal responses to stress. As IL-6 induces acute-phase proteins along with glucocorticoids from the adrenal, and regulates the secretion of various hormones from neuroendocrine and endocrine tissues, it is possible that stress-induced increase in plasma IL-6 contributes to the maintenance of homeostasis.

During lactation, endocrine function is altered and stress responses are dampened. Stress effects on immune function are partially determined by endocrine factors; therefore, we assessed whether stress similarly alters immune function during lactation. Sprague-Dawley rats were conditioned by exposure to a tone paired with foot shock (2 sessions, 16 shocks each) prior to breeding or were left undisturbed. Lactating (day 10) (Lac) and nonlactating diestrous virgin controls (C) were killed immediately after reexposure to the tone or removal from their home cage. Plasma corticosterone stress responses were dampened in Lac relative to C animals. Peripheral blood lymphocyte proliferation to T cell receptor antibody stimulation was reduced to a similar extent in both experimental groups. Conditioned stress reduced splenocyte proliferation and increased nitrite accumulation in C animals, but not in Lac animals. Mesenteric lymph node lymphocyte proliferation was significantly increased after stress in Lac compared with C animals. Both plasma interleukin-6 (IL-6) and phytohemagglutinin-stimulated splenic IL-6 production were increased in Lac animals compared with C animals after stress exposure. These data indicate that stress-induced alterations may be determined by different regulatory mechanisms within immune compartments and that these effects depend on the physiological state of the organism.

No abstract