The present work demonstrates that marked sex differences occur in the reaction of immune system during fasting; the extent of reaction was smaller with females than with males. Kinetic analysis revealed that estradiol was principally responsible for the observed sex differences.
The major response to stress is the activation of the HPA axis [24
]. This system involves the production and release of CRH followed by the production and secretion of proopiomelanocortin (POMC) peptides. ACTH induces the production and secretion of cortisol, a powerful anti-inflammatory factor. During stress, autonomic nervous system (ANS) also exerts systemic effects on immune system by inducing the secretion of IL-6 in the circulation [25
]. Despite its inherent inflammatory activity, IL-6 plays a major role in the overall control of inflammation by stimulating glucocorticoid secretion [26
] and by suppressing the secretion of TNF-α and IL-1. Furthermore, catecholamines inhibit IL-12 and stimulate IL-10 secretion [28
]. The combined effects of glucocorticoids and catecholamines on the monocyte/macrophage and dendritic cells inhibit innate immunity and Th1-related cytokines, such as IFN-γ and IL-12, and stimulate Th2-related cytokines, such as IL-10 [29
The present work shows that the plasma level of cortisol and IL-10 increased during the fasting stress. The strong increase in plasma cortisol in male seems to elicit the sex difference in the amount of production of IL-10. Preliminary experiment revealed that lipoplysaccharide (LPS) levels in the blood significantly increased during the fasting, suggesting the translocation of microflora across the intestinal mucosa (data mot shown). Consistent with previous observation [30
], the increase in plasma IFN-γ was followed by the decrease in IL-10 on day 3 after fasting.
The mucosal IgA, a Th2-related antibody, also increased during the fasting. As a result, B cells in the intestinal mucosa were activated by the increased cortisol. Since the mucosal expression of IgA reflects the increased immunity against the invasion of intestinal pathogens, the increase in the plasma levels of LPS might be the cause of the increased IgA in the intestine [31
]. The increased IgA in the mucosal layer might participate in the increased activity to suppress pathogens invading from intestinal lumen under the fasting conditions.
The present works shows that the stress elicited by fasting stimulated the HPA axis and immunological reactions more markedly in male than in females. The reaction in the females was increased by the administration of testosterone. Furthermore, the immunological reaction of the OVX females administered with testosterone was similar to that of the males. The reaction of male animals was reduced by administrating estradiol to a level comparable to that of the CAX females administered with estradiol. Furthermore, apoptosis of Leydig cells in the testis was induced by fasting with concomitant decrease in plasma levels of testosterone. In contrast, apoptotic cells were not observed in the ovary of fasted females despite the decrease in plasma estradiol. This observation suggested that sex hormones are responsible for the sex differences in the immunological reactions to fasting stress.
Several studies suggested that estradiol plays a role in the enhancement of stress responses in OVX rats that showed the enhancement of the HPA response to stress after treatment with estradiol [32
]. Female rats show enhanced HPA response in the proestrus cycle when plasma levels of estrogen and progesterone are low [34
]. Since plasma levels of estradiol and testosterone decrease during the exposure to fasting stress, their decrease might reflect the stimulation of the HPA axis. However, the detailed mechanism request further study.
Previous studies have indicated that the sex difference in the susceptibility to stress might result from sex difference in cytokine production upon stimulation by autoantigens in male and female. Enhanced production of Th2-related cytokines and suppressed expression of Th1 related cytokines have been observed with males as compared with females [35
]. Since plasma levels of testosterone decreased markedly during the fasting, the activation of Th2 reactions does not last for a long time and, hence, Th1 type reaction increased during the long fasting stress.
These observations suggest that the HPA axis was activated by fasting to cause immunomodulation in which Th2 type reaction predominate during the initial time particularly in male. In contrast, the response to fasting stress occurs mildly in females than in male, thereby immunological reactions occur more mildly in the former than in the latter. The marked sex difference in the immunological responses to fasting might favor the animals to survive under environment where foods were always limited strongly.