S30
Interaction between Hormones and the Immune System H. Weicker, E. Werle Department of Sports and Performance Medicine, Medical Clinic and Policlinic, University of Heidelberg, Heidelberg,Germany
Introduction
H. Weicker, E. Werle, Interaction between Hormones and the Immune System. mt J Sports Med, Vol l2,Suppl l,ppS3O—S37, 1991. After a short introduction into the general topic,
the catecholamine-induced increase of leukocytes in
which the granulocytes are predominant after short-term exercise is discussed. The reduction of lymphocytes is associated with work-dependent cortisol increase after long-
term exercise or I h after strenuous work. The catecholamine-stimulated lymphocytes increase could be explained by the liberation of the cells from the endothelial vessel wall after catecholamine interaction with the 3adrenoceptors and by mobilization from lymph nodes and spleen after 3-adrenergic stimulation. Catecholamines reduce the proliferation of lymphocytes and the degranulation of mast cells, preventing hypersensitivity reaction due to inhibited mediator liberation. The influence of cortisol and cytokines and vice versa is discussed. The hormonal changes after runs of different intensities and duration are demonstrated; they show an interaction with immunological regulation. The neuroimmune modulation after physical and psychological stress also has to be considered in immune regulation since under this condition the secretion of encephalins, endorphins, ACTH, and cortisol is increased. The significance of enhanced vasopressin secretion causing postural fainting by vagovasal reaction indicates also the effect of a neuropeptide which is related to immunological reactions. In the changes of lymphocyte subclasses, the homing effect of these cells should be regarded. Advices which can improve the immunologic behaviour, avoiding susceptibility to infections by well-conducted training regimens and adequate periods of regeneration time, are necessary. The multifold mechanisms involved in the immune regulation and the interaction with several hormonal and metabolic changes caused by exercise make it diffucult to give, at the present time, well-founded practical pieces of advice; it needs more work and well-conducted studies of exercise and competition.
Key words Hormonal immunologic modulation, leuko-
cytes, lymphocytes, catecholamines, cortisol, neuropeptides, cytokines, lymphocytes subpopulation Int.J. Sports Med. 12(1 991)S30—S37
Georgmieme Verlag Stuttgart New York
Advances in immunology, especially in research on the cell-mediated system and neuroimmune modulation (NIM), indicate that exercise and training might have an impact on these functions (1, 2, 6, 7, 11, 29). However, it has not yet been definitively explored if sports activity, especially at the level of high top performance, will foster or impair immunologic resistance (3, 7, 18). The complexity of the immune system, involving antigen presentation and activation of 1, B,
and NK cells, formation of memory cells, secretion of cytokines and prostaglandins and activation of the complement cascade, impede the understanding of the influence of exercise on immune regulation (1, 6, 11). Investigations on the relationship between hormones and the immune system and especially on the interaction of neuropeptides with the immunologic network and the central nervous system (CNS) give new insights into the current research on NIM (2). However, its sig-
nificance for the human organism has not yet been fully clarified since most of the results have been obtained in animal
trials. Investigations on hormone regulation during exercise and training have been mainly focused on hormonal-metabolic, but less on hormonal-immunologic communication. Furthermore, the experimental designs described in publications differ in methods, training, and exercise regimens of trained and untrained subjects so that it is difficult to compare the results reported (3, 7,8, 13, 18,21,23,24,27, 31, 35, 36, 39). Therefore, this paper will emphasize the influence of wellknown hormones such as catecholamines, cortisol, insulin, ACTH, growth hormone, and vasopressin on immunologic regulation during work. The neuropeptides will be briefly discussed with regard to their importance in circadian and seasonal rhythms as well as during strain and recovery (14, 22, 32). Before we refer in detail to changes in the immune reaction induced by hormone stimulation during exercise, it seems worthwhile to take a closer look at leukocytosis after exercise since this well-known mechanism demonstrates the difficulty in interpreting such a simple finding. Leukocytosis and
Catecholamines
After short-term exercise the extent of leukocyte increase corresponds to work intensity, in which the train-
ing state of the subject has to be considered. The ratio of granulocytes and lymphocytes does not change substantially (3). The work-dependent catecholamine increase probably plays a major role in initiating leukocytosis via f3-adrenocep-
tors, which has been proved by epinephrine injection in physiological concentrations (4). Catecholamines might reduce endothelial adhesion of leukocytes to the vessel walls, and 3-adrenoceptor antagonists abolish to a certain extent this
Downloaded by: University of British Columbia. Copyrighted material.
Abstract
IntJ.SportsMed. 12 (1991) S31
Interaction between Hormones and the Immune System
tion on the proopio melanocortin (P0 MC) system stimulating endorphin, encephalin, and ACTH release. Therefore, central
catecholamine liberation caused by physical and psychological stress can activate both the hypothalamic pituitary and the lymphoid adrenal axis since lymphocytes are equipped with ACTH and opioid receptors and produce these sub-
] DIR
stances (2, 29).
reactions
Catecholamines inhibit the degranulation in mast cells and basophilic granulocytes, thereby diminishing the release of mediator substances, e. g., histamine or serotonin, and consequently the hypersensitivity reaction is less pronounced. Since sulfatases are released together with mediator substances from activated mast cells, catecholamine sulfates in the neighborhood of mast cells are deconjugated to
killing
IgER
free catecholamines, a reaction which might also reduce reactions
IgER
further degranulation (Fig. 1) (1, 6).
Leukocytosis and Cortisol The increase in white blood cells (WBC) 2—3 h
gE, gOl Fc,R
after short-term maximal work or immediately after long-en-
durance exercise such as marathon runs differs from catecholamine-induced leukocytosis by the presence of lymphopenia and eosinopenia, probably caused by the work-dependent increase in cortisol (3, 21, 27, 31, 38). It might enhance Fig. 1 The regulatory effect of I helper cells (TH1, TH2) on type IV leukocyte liberation from bone marrow, but it also mediates (delayed type, DT!-I) and type I hypersensitivity. The cytokines such lymphocyte distribution in the body (6). Leukocytes rise 2 h as interleukins (IL), interferons (PEN), and tumor necrosis factor after oral application or immediately after injection of corti(TNE) act on B cells (B), macrophages (MO), eosinophils (E), mast sol. Yu reported that cortisol injections 2 or 5 h before exercise cells, and target cells modulating antibody-dependent (ADCC) and cell-mediated cytotoxicity and inflammatory mediator release (1). were followed by leukocytosis, lymphopenia, and eosinopenia already immediately after short maximal exercise (41). On the other hand, cortisol is one of the best explored hormones with impact on immune regulation (6). Its well-known catecholamine-induced leukocytosis (3). But on the other hand, it has to be taken into consideration that spleen, lymph immune suppressive and anti-inflammatory efficiency might nodes, liver, and thymus also carry adrenoceptors and their be explained by the interrelationship between cortisol and cystimulation during exercise might intensify leukocyte release tokines, which has been recently discovered (34) (Fig. 2). Inhifrom these organs. Furthermore, catecholamines enhance the bition of IL-I reduces stimulation of CD4 cells and IL-2 reexpression. As a result, IL-2 formation in CD4+ and proliferation of CD3, CD4 , and CD8 lymphocytes by a- ceptor CD8 + cells is diminished and lymphocyte proliferation imadrenergic stimulation, whereas 3-adrenergic impulses followed by intracellular adenylate cyclase stimulation inhibit paired. Cortisol does not only affect the T-cell system since B, proliferation, which is more pronounced in CD4+ than in NK, and memory cells depend on the activation of CD4 cells CD8 cells (6, 21,40). These findings might explain the differ- by monocyte IL-l and their autocrine stimulation by IL-2. In ent leukocyte counts obtained during circadian rhythms, but this way, cortisol modulates proliferation, antibody formaalso at rest and after work (32). The inhibition of T-cell pro- tion, and stimulation by mitogens. It might also prevent 'y-inliferation depends not only on the concentration of cate- terferon (IFN-'y) from activating monocytes and macrophages cholamines in the blood after exercise but also on the number in the primary antigen elimination, an important step which of 3-adrenoceptors on lymphocytes, which is dependent on suppresses the propagation of viral or bacterial infections. the duration and type of training performed by the athlete (17), Furthermore, the extent of lymphocyte cytolysis corresponds but increases in most cases after strenuous work (39). How- to the number of cortisol receptors, as has been discovered in ever, considerable individual variations are found, a fact that the treatment of leukemia (Dr. H. D. Ho, personal comhas not yet been clearly elucidated. Landmann et al. reported munication). The cytolytic efficiency of cortisol is reduced in that leukocytosis caused by an increase in granulocytes and adult cells due to their lower receptor numbers (6). The callymphocytes, NK and B cells as well as changes in lymphocyte cium influx through the cell membrane is enhanced by cortisol subsets corresponds to the catecholamine augmentation after and activates endonuclease, which impairs protein synthesis submaximal bicycle exercise, which was higher than after on molecular basis, initiating both the immunologic and antiemotional strain caused by the color-word-conflict test (21). inflammatory efficacy (6). Cortisol is a strong IL-I inhibitor, No substantial cortisol increase was found immediately after but on the other hand, IL-i stimulates cortisol production by the tests. After epinephrine injection, Crary et a!. found similar activation of corticotropin-releasing factor (CRF) followed by ACTH liberation from the pituitary gland, which enhances the changes, but no increase in B cells (4, 40). adrenal cortisol secretion (2, 29, 34). Under stress, the hyLiberation of dopamine and norepinephrine pothalamic pituitary adrenal axis, in which IL-i seems to be from syrnpathoadrenergic neurons in brain has a trigger func- important, is enforced by hormones and neuropeptides. Both
Downloaded by: University of British Columbia. Copyrighted material.
type I hypersensitivity
S32 mt. J. Sports Med. 12(1991) 800
H. Weicker, E. Werle
A
B
600
I
E
I 400 F-
I I
I
Fig. 2 Increase in ACTH and corticosterone serum levels in mice by human recombinant (rlL-i) or purified human monocyte (Mo-IL-i) interleukin-i. Two hours after intraperitoneal application of IL-i, both ACTH and corticosterone levels were significantly higher (p
Interaction between Hormones and the Immune System H. Weicker, E. Werle Department of Sports and Performance Medicine, Medical Clinic and Policlinic, University of Heidelberg, Heidelberg,Germany
Introduction
H. Weicker, E. Werle, Interaction between Hormones and the Immune System. mt J Sports Med, Vol l2,Suppl l,ppS3O—S37, 1991. After a short introduction into the general topic,
the catecholamine-induced increase of leukocytes in
which the granulocytes are predominant after short-term exercise is discussed. The reduction of lymphocytes is associated with work-dependent cortisol increase after long-
term exercise or I h after strenuous work. The catecholamine-stimulated lymphocytes increase could be explained by the liberation of the cells from the endothelial vessel wall after catecholamine interaction with the 3adrenoceptors and by mobilization from lymph nodes and spleen after 3-adrenergic stimulation. Catecholamines reduce the proliferation of lymphocytes and the degranulation of mast cells, preventing hypersensitivity reaction due to inhibited mediator liberation. The influence of cortisol and cytokines and vice versa is discussed. The hormonal changes after runs of different intensities and duration are demonstrated; they show an interaction with immunological regulation. The neuroimmune modulation after physical and psychological stress also has to be considered in immune regulation since under this condition the secretion of encephalins, endorphins, ACTH, and cortisol is increased. The significance of enhanced vasopressin secretion causing postural fainting by vagovasal reaction indicates also the effect of a neuropeptide which is related to immunological reactions. In the changes of lymphocyte subclasses, the homing effect of these cells should be regarded. Advices which can improve the immunologic behaviour, avoiding susceptibility to infections by well-conducted training regimens and adequate periods of regeneration time, are necessary. The multifold mechanisms involved in the immune regulation and the interaction with several hormonal and metabolic changes caused by exercise make it diffucult to give, at the present time, well-founded practical pieces of advice; it needs more work and well-conducted studies of exercise and competition.
Key words Hormonal immunologic modulation, leuko-
cytes, lymphocytes, catecholamines, cortisol, neuropeptides, cytokines, lymphocytes subpopulation Int.J. Sports Med. 12(1 991)S30—S37
Georgmieme Verlag Stuttgart New York
Advances in immunology, especially in research on the cell-mediated system and neuroimmune modulation (NIM), indicate that exercise and training might have an impact on these functions (1, 2, 6, 7, 11, 29). However, it has not yet been definitively explored if sports activity, especially at the level of high top performance, will foster or impair immunologic resistance (3, 7, 18). The complexity of the immune system, involving antigen presentation and activation of 1, B,
and NK cells, formation of memory cells, secretion of cytokines and prostaglandins and activation of the complement cascade, impede the understanding of the influence of exercise on immune regulation (1, 6, 11). Investigations on the relationship between hormones and the immune system and especially on the interaction of neuropeptides with the immunologic network and the central nervous system (CNS) give new insights into the current research on NIM (2). However, its sig-
nificance for the human organism has not yet been fully clarified since most of the results have been obtained in animal
trials. Investigations on hormone regulation during exercise and training have been mainly focused on hormonal-metabolic, but less on hormonal-immunologic communication. Furthermore, the experimental designs described in publications differ in methods, training, and exercise regimens of trained and untrained subjects so that it is difficult to compare the results reported (3, 7,8, 13, 18,21,23,24,27, 31, 35, 36, 39). Therefore, this paper will emphasize the influence of wellknown hormones such as catecholamines, cortisol, insulin, ACTH, growth hormone, and vasopressin on immunologic regulation during work. The neuropeptides will be briefly discussed with regard to their importance in circadian and seasonal rhythms as well as during strain and recovery (14, 22, 32). Before we refer in detail to changes in the immune reaction induced by hormone stimulation during exercise, it seems worthwhile to take a closer look at leukocytosis after exercise since this well-known mechanism demonstrates the difficulty in interpreting such a simple finding. Leukocytosis and
Catecholamines
After short-term exercise the extent of leukocyte increase corresponds to work intensity, in which the train-
ing state of the subject has to be considered. The ratio of granulocytes and lymphocytes does not change substantially (3). The work-dependent catecholamine increase probably plays a major role in initiating leukocytosis via f3-adrenocep-
tors, which has been proved by epinephrine injection in physiological concentrations (4). Catecholamines might reduce endothelial adhesion of leukocytes to the vessel walls, and 3-adrenoceptor antagonists abolish to a certain extent this
Downloaded by: University of British Columbia. Copyrighted material.
Abstract
IntJ.SportsMed. 12 (1991) S31
Interaction between Hormones and the Immune System
tion on the proopio melanocortin (P0 MC) system stimulating endorphin, encephalin, and ACTH release. Therefore, central
catecholamine liberation caused by physical and psychological stress can activate both the hypothalamic pituitary and the lymphoid adrenal axis since lymphocytes are equipped with ACTH and opioid receptors and produce these sub-
] DIR
stances (2, 29).
reactions
Catecholamines inhibit the degranulation in mast cells and basophilic granulocytes, thereby diminishing the release of mediator substances, e. g., histamine or serotonin, and consequently the hypersensitivity reaction is less pronounced. Since sulfatases are released together with mediator substances from activated mast cells, catecholamine sulfates in the neighborhood of mast cells are deconjugated to
killing
IgER
free catecholamines, a reaction which might also reduce reactions
IgER
further degranulation (Fig. 1) (1, 6).
Leukocytosis and Cortisol The increase in white blood cells (WBC) 2—3 h
gE, gOl Fc,R
after short-term maximal work or immediately after long-en-
durance exercise such as marathon runs differs from catecholamine-induced leukocytosis by the presence of lymphopenia and eosinopenia, probably caused by the work-dependent increase in cortisol (3, 21, 27, 31, 38). It might enhance Fig. 1 The regulatory effect of I helper cells (TH1, TH2) on type IV leukocyte liberation from bone marrow, but it also mediates (delayed type, DT!-I) and type I hypersensitivity. The cytokines such lymphocyte distribution in the body (6). Leukocytes rise 2 h as interleukins (IL), interferons (PEN), and tumor necrosis factor after oral application or immediately after injection of corti(TNE) act on B cells (B), macrophages (MO), eosinophils (E), mast sol. Yu reported that cortisol injections 2 or 5 h before exercise cells, and target cells modulating antibody-dependent (ADCC) and cell-mediated cytotoxicity and inflammatory mediator release (1). were followed by leukocytosis, lymphopenia, and eosinopenia already immediately after short maximal exercise (41). On the other hand, cortisol is one of the best explored hormones with impact on immune regulation (6). Its well-known catecholamine-induced leukocytosis (3). But on the other hand, it has to be taken into consideration that spleen, lymph immune suppressive and anti-inflammatory efficiency might nodes, liver, and thymus also carry adrenoceptors and their be explained by the interrelationship between cortisol and cystimulation during exercise might intensify leukocyte release tokines, which has been recently discovered (34) (Fig. 2). Inhifrom these organs. Furthermore, catecholamines enhance the bition of IL-I reduces stimulation of CD4 cells and IL-2 reexpression. As a result, IL-2 formation in CD4+ and proliferation of CD3, CD4 , and CD8 lymphocytes by a- ceptor CD8 + cells is diminished and lymphocyte proliferation imadrenergic stimulation, whereas 3-adrenergic impulses followed by intracellular adenylate cyclase stimulation inhibit paired. Cortisol does not only affect the T-cell system since B, proliferation, which is more pronounced in CD4+ than in NK, and memory cells depend on the activation of CD4 cells CD8 cells (6, 21,40). These findings might explain the differ- by monocyte IL-l and their autocrine stimulation by IL-2. In ent leukocyte counts obtained during circadian rhythms, but this way, cortisol modulates proliferation, antibody formaalso at rest and after work (32). The inhibition of T-cell pro- tion, and stimulation by mitogens. It might also prevent 'y-inliferation depends not only on the concentration of cate- terferon (IFN-'y) from activating monocytes and macrophages cholamines in the blood after exercise but also on the number in the primary antigen elimination, an important step which of 3-adrenoceptors on lymphocytes, which is dependent on suppresses the propagation of viral or bacterial infections. the duration and type of training performed by the athlete (17), Furthermore, the extent of lymphocyte cytolysis corresponds but increases in most cases after strenuous work (39). How- to the number of cortisol receptors, as has been discovered in ever, considerable individual variations are found, a fact that the treatment of leukemia (Dr. H. D. Ho, personal comhas not yet been clearly elucidated. Landmann et al. reported munication). The cytolytic efficiency of cortisol is reduced in that leukocytosis caused by an increase in granulocytes and adult cells due to their lower receptor numbers (6). The callymphocytes, NK and B cells as well as changes in lymphocyte cium influx through the cell membrane is enhanced by cortisol subsets corresponds to the catecholamine augmentation after and activates endonuclease, which impairs protein synthesis submaximal bicycle exercise, which was higher than after on molecular basis, initiating both the immunologic and antiemotional strain caused by the color-word-conflict test (21). inflammatory efficacy (6). Cortisol is a strong IL-I inhibitor, No substantial cortisol increase was found immediately after but on the other hand, IL-i stimulates cortisol production by the tests. After epinephrine injection, Crary et a!. found similar activation of corticotropin-releasing factor (CRF) followed by ACTH liberation from the pituitary gland, which enhances the changes, but no increase in B cells (4, 40). adrenal cortisol secretion (2, 29, 34). Under stress, the hyLiberation of dopamine and norepinephrine pothalamic pituitary adrenal axis, in which IL-i seems to be from syrnpathoadrenergic neurons in brain has a trigger func- important, is enforced by hormones and neuropeptides. Both
Downloaded by: University of British Columbia. Copyrighted material.
type I hypersensitivity
S32 mt. J. Sports Med. 12(1991) 800
H. Weicker, E. Werle
A
B
600
I
E
I 400 F-
I I
I
Fig. 2 Increase in ACTH and corticosterone serum levels in mice by human recombinant (rlL-i) or purified human monocyte (Mo-IL-i) interleukin-i. Two hours after intraperitoneal application of IL-i, both ACTH and corticosterone levels were significantly higher (p
