Hormones Mediating Stressinduced Changes in Blood Leukocyte Numbers

The catecholamines epinephrine and norepinephrine and the glucocorti-coid hormones have been identified as the major endocrine mediators of stress-induced changes in leukocyte distribution (Fauci and Dale, 1974; Schedlowski et al., 1993a, 1993b; Dhabhar et al., 1995a; Benschop et al., 1996; Dhabhar et al., 1996). Studies have revealed that stress-induced changes in leukocyte distribution are mediated by hormones released by the adrenal gland (Dhabhar et al., 1996; Dhabhar and McEwen, 1999b).Adrenalectomy (which eliminates the corticosterone and epinephrine stress response) has been shown to reduce the magnitude of the stress-induced changes in blood leukocyte numbers. (Dhabhar et al., 1996; Dhabhar and McEwen, 1999b). Cyanoketone treatment, which virtually eliminates the corticosterone stress response, also virtually eliminates the stress-induced decrease in blood lymphocyte numbers, and significantly enhances the stress-induced increase in blood neutrophil numbers (Dhabhar et al., 1996). Several other studies have shown that glucocorticoid treatment induces changes in leukocyte distribution in mice (Dougherty and White, 1945; Spain and Thalhimer, 1951;

Cohen, 1972; Zatz, 1975), guinea pigs (Fauci, 1975), rats (Ulich et al., 1988; Miller et al., 1994; Dhabhar et al., 1996), rabbits (Miller et al., 1994), and humans (Fauci and Dale, 1974; Fauci, 1976; Onsrud and Thorsby, 1981).

Because adrenal steroids act at two distinct receptor subtypes that show a heterogeneity of expression in immune cells and tissues (Spencer et al., 1990,1991; Miller et al., 1990,1991,1992,1993; Dhabhar et al., 1993,1995b, 1996), Dhabhar et al. investigated the role played by each receptor subtype in mediating changes in leukocyte distribution (Dhabhar et al., 1996).Acute administration of aldosterone (a specific type I adrenal steroid receptor agonist) to adrenalectomized animals did not have a significant effect on blood leukocyte numbers. In contrast, acute administration of corticos-terone (the endogenous type I and type II receptor agonist) or RU28362 (a specific type II receptor agonist) to adrenalectomized animals induced changes in leukocyte distribution that were similar to those observed in intact animals during stress. These results suggest that corticosterone, acting at the type II adrenal steroid receptor, is a major mediator of the stress-induced decreases in blood lymphocyte and monocyte distribution. Taken together, these studies show that stress and glucocorticoid hormones induce a significant decrease in blood lymphocyte numbers when administered under acute or chronic conditions.

Apart from glucocorticoids, studies have also demonstrated the importance of catecholamine hormones in mediating stress-induced changes in blood leukocyte distribution in rodents and humans (Benshop et al., 1993, 1996; Schedlowski et al., 1993b; Carlson et al., 1997; Mills et al., 1998; Mills et al., 2001; Redwine et al., 2003; Engler et al., 2004). In apparent contrast with glucocorticoid hormones, catecholamine hormones have been shown to increase blood leukocyte numbers in rats (Harris et al., 1995) and humans (Landmann et al., 1984). On closer examination, it is observed that after adrenaline or noradrenaline administration, neutrophil and NK cell numbers increase rapidly and dramatically whereas T- and B-cell numbers decrease (Tonnesen et al., 1987; Landmann, 1992; Schedlowski et al., 1993b; Benschop et al., 1996). Carslon et al. have shown that catecholamine pre-treatment results in increased accumulation of lymphocytes in the spleen and lymph nodes (Carlson et al., 1997), which would be in agreement with a catecholamine-induced decrease in lymphocytes in the blood. By acutely administering epinephrine, norepinephrine, selective a and P adrenergic receptor agonists, or corticosterone to adrenalectomized animals, researchers have shown that increases in blood granulocyte numbers may be mediated by the a1 and P adrenergic receptors and are counteracted by corticosterone acting at the type II adrenal steroid receptor (Dhabhar and McEwen, 1999b). Increases in lymphocytes may be mediated by the a2 receptor, whereas decreases in lymphocytes may be mediated by P adren-ergic and type II adrenal steroid receptors (Dhabhar and McEwen, 1999b).

Therefore, the absolute number of specific blood leukocyte subpopulations may be significantly affected by the ambient concentrations of epi-

nephrine, norepinephrine, and corticosterone. Differences in concentrations and combinations of these hormones may explain reported differences in blood leukocyte numbers during different stress conditions (e.g., short-versus long-duration acute stress, acute versus chronic stress) and during exercise.

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