immune system suppression, for example decreased lymphocyte proliferation and cytokine production, damage to the hippocampus, and hypertension (Dickerson and Kemeny, 2004). The vasoconstrictive and immunological impact of the activation of the HPA axis is of relevance for sickle cell disease.

The effect of cortisol on tissues is mediated by the glucocorticoid receptor (GR) through direct binding to hormone-responsive elements in the RNA or by interactions with, and modulation of, other transcription factors (Wüst et al., 2004b). The response of a cell to cortisol is a function of the level of the steroid and its GC sensitivity. Variants of the GR gene (located on chromosome 5, locus 5q31) affect sensitivity (Wüst et al., 2004b). Support has been provided for the hypothesis that common polymorphisms in the GR gene may have modulating effects on the HPA response to psychological stress. In a recent study, the impact of three GR gene polymorphisms (BclI RFLP, N363S, and ER22/23EK) on cortisol and ACTH responses to psychological stress and pharmacological stimulation was assessed (Wüst et al., 2004b). In comparison to subjects with two wild-type alleles, 363S carriers showed a significant increased salivary cortisol response to stress whereas the cortisol response of the BclI homozygotes was diminished. This study provides evidence that common polymorphisms of a single gene impact HPA regulation and contribute to the individual variability in response to psychological stress. The impact of genetic factors on HPA axis activity was reported from findings of twin studies and association studies with polymorphisms in the GR gene (Wüst et al., 2004a). In addition, a number of polymorphisms were identified as good candidate genes for future studies (Wüst et al., 2004a).

Evidence suggests that the GCs act through genetic mechanisms, to modify transcription of key regulatory proteins, and by non-genetic mechanisms on cell signaling processes that have a more rapid impact on homeostatic regulation (Herman et al., 2003). The HPA mediated response to stressful stimuli differ depending upon whether the threat to homeostasis is “real” or “predicted.” By real stressor is meant stimuli that are recognized by somatic, visceral, or circumventricular sensory pathways as a challenge to homeostasis. These stimuli include hormonal signals, such as renin-angiotensin, visceral or somatic pain, or humoral inflammatory signals such as blood-borne cytokines signaling infection (Herman et al., 2003). In addition to these “reactive” responses, GC responses can occur in “anticipation” of homeostatic disruption under situations in which threat may be predicted or associated with learned experience. The anticipatory responses are under the control of limbic regions such as the hippocampus, amygdale, and prefrontal cortex (Herman et al., 2003). These two systems act together in an integrated, hierarchal manner. The reactive pathway evokes direct PVN activation whereas the anticipatory pathway involves forebrain



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