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Acta Microbiologica et Immunologica Hungarica, 61 (3), pp. 241–260 (2014) DOI: 10.1556/AMicr.61.2014.3.1

HORMONES IN THE IMMUNE SYSTEM AND THEIR POSSIBLE ROLE. A CRITICAL REVIEW

GYÖRGY CSABA*

Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary

(Received: 23 April 2014; accepted: 20 May 2014)

Immune cells synthesize, store and secrete , which are identical with the hormones of the endocrine glands. These are: the POMC hormones (ACTH, endor- phin), the system hormones (TRH, TSH, T3), growth (GH), , , , serotonin, , GnRH, LHRH, hCG, renin, VIP, ANG II. This means that the immune cells contain all of the hormones, which were searched at all and they also have receptors for these hormones. From this point of view the immune cells are similar to the unicells (Tetrahymena), so it can be supposed that these cells retained the properties characteristic at a low level of phylog- eny while other cells during the accumulated to form endocrine glands. In contrast to the glandular endocrine cells, immune cells are polyproducers and polyreceivers. As they are mobile cells, they are able to transport the stored hormone to different places (packed transport) or attracted by local factors, accumulate in the neighborhood of the target, synthesizing and secreting hormones locally. This is tak- ing place, e.g. in the case of endorphin, where the accumulating immune cells calms pain caused by the . The targeted packed transport is more economical than the hormone-pouring to the circulation of glandular endocrines and the tar- geting also cares the other -bearing cells timely not needed the effect. Mostly the immune-effects of immune-cell derived hormones were studied (except endor- phin), however, it is not exactly cleared, while the system could have scarcely studied important roles in other cases. The evolutionary aspects and the known as well, as pos- sible roles of immune- and their hormones are listed and discussed.

Keywords: immunoendocrinology, hormones, immune cells, packed trans- port, immune evolution, endocrine evolution

* E-mail: [email protected]

1217-8950/$20.00 © 2014 Akadémiai Kiadó, Budapest 242 CSABA

The basic role of the immune system is the discrimination between the self and non-self and recognizing the non-self, its destruction for protecting the - ism from their harmful effects. The non-self can be present inside the by an alteration of self cells or tissues, in this case the homeostasis of the organism is saved by the action of the immune system. In other case, the non-self – , or parasites – offend the organism from outside and the cells of the im- mune system try to destroy it, saving the integrity and health of the organism. Till the last decades of the last century this double function dominated our imagina- tions on the role of the immune system, however, in this time Blalock and his team observed [1, 2] that the immune cells contain, produce and secrete hormones char- acteristic to the endocrine system. From this time a mass of investigations were taking place and practically all of the hormones produced by the glandular endo- crine system were found also in the immune cells. The hormones secreted by the immune cells are influencing the immune system itself, however, they can partici- pate in the regulation of cells of other systems in the organism. Considering that the whole mass of – which are the primary source of the hormones mentioned – is approximately similar to the brain or the [3], the influence of the immune-produced hormones cannot be neglected. The purpose of this review to introduce the presence of hormones in the immune cells and the discussion on their known or presumable functions.

Endorphin, inflammation and pain

The most thoroughly studied hormones of the immune cells are those which in our earlier knowledge are produced solely by the and among them the outstanding is the endorphin. The proopiomelanocortin (POMC) is present and working in the pitu- itary gland, creating the possibility of the production of POMC-derived hormones. After processing the POMC , these are the adrenocorticotropin (ACTH), melanocortin, lipotropin and endorphin. The POMC gene is also working in the immune cells (lymphocytes (T and B alike) [4–8], , , and mast cells), and this can be found from the amphibians [9] to man [10]. After the processing of the basic , endorphin is packed in mem- brane bound secretory vesicles [11] and can be released when it is needed. The im- mune cells also have receptors for endorphin [12, 13], which transmit the signal for the immune machinery [1], promoting the production of and influ- encing the immune functions, as the migration of granulocytes (which

Acta Microbiologica et Immunologica Hungarica 61, 2014 HORMONES IN THE IMMUNE SYSTEM 243 is enhanced [14]), or the survival of them [15], or influencing the lymphocytes’ synthesis [16], chemotactic activity [17], or NK cell activity [18]. The immuno-derived endorphin mediates the immuno-enhancing effect of melatonin [19]. The hormone also can compensate the negative immunological effect of [20]. The immunological effects of endorphin seem to be age-de- pendent and the hormone could play a role in the immunodepression during aging [21, 22]. The investigations on the immunological effects of endorphin are relatively scarce, which can be explained by the specific painkilling effect of the hormone which is in the forefront of research. During inflammation the concentration of peptides rapidly elevates in the blood circulation [15], however, this can be originated from the pituitary as well as from the immune cells. The most interest- ing and specific are the local production. In the early phase of inflammation the granulocytes are releasing the [23]. Later lymphocytes and other immune cells are producing the pain calming hormone [24] which, as well as, the granulo- cytes and mast cells [25, 26] have corticotrophin releasing hormone (CRH) R1 and R2 receptors and the immune cells similarly to the brain cells, synthesize CRH [27, 28]. However, it is not known whether CRH is always needed for the release of endorphin, or not. During inflammation, among lymphocytes, the acti- vated/memory T cells (CD4+/CD45RC-) contain endorphin and these cells are ac- cumulated in the inflamed area [29–32] and have CRH receptors. CRH release is activated by the of inflammation [27, 33]. In cyclosporine immuno- suppressed the anti-nociceptive effect of CRH is not manifested, because of the absence of endorphin-producing immune cells, however, after injecting concanavalin A activated donor immune cells, the antinociception is working [34]. For antinociception the effect on the central terminals is not needed, the local effect (on peripheral sensory terminals) seems to be enough [35]. Immune cells produce and contain not only endorphin, as pain killer but also met-enkephalin and dynorphin, however, endorphin is the dominant factor [36]. It is likely that the main role of endorphin (opioids) in the immune cells is not the regulation of the immune functions, but the pain-killing. The endorphin producing immune cells are accumulating in the inflamed area by migration from the neighborhood or the nodes. The cells have receptors for CRH which helps the release of the hormone [37], however, cytokines also promote the re- lease. For the release presence of calcium is also needed. Mostly T memory cells are participating in the reaction, naïve cells – not containing opioids – are not pres- ent [38]. Although CRH seems to be the most important regulator of endorphin re-

Acta Microbiologica et Immunologica Hungarica 61, 2014 244 CSABA lease, other factors (hormones) also can influence it, e.g. glucocorticoids (dexa- methasone), which can inhibit the -derived endorphin [39], , gonadotropin and epidermal , which elevate the endorphin production [40], however, insulin and biogenic amines administered in vitro are indifferent or hardly effective from this point of view [41, 42]. There is also a pos- sibility of pharmacological effects on the endorphin content and this is parallel in the immune cells and the central [43]. Considering the facts mentioned above, not only a pain-killer molecule is produced by the immune cells, but there is a pain killer system with different regu- lators (stimulators and inhibitors) with anti-nociceptive effects, activated by the stress caused by inflammation.

The adrenocorticotropic hormone (ACTH)

After the processing of the POMC in the immune cells ACTH is also pro- duced [4, 44]. Considering its amino sequence as well as molecular weight, antigenicity and bioactivity, this molecule is identical with the ACTH hormone produced by the pituitary gland [1, 45]. The presence of the hormone is demon- strated in the immune cells from amphibians to man [9, 10, 46]. It can increase B lymphocyte proliferation [47] and can be a paracrine or autocrine regulator of im- mune functions [48]. During pregnancy the ACTH secretion of lymphocytes ele- vates up to the 600% of that in non-pregnant animals, in bovine experiments [49]. There is a gender dependence of ACTH content in immune cells [50]. Months af- ter a perinatal stress the ACTH content of immune cells is also elevated [51]. An intervention into the genetic system (knock-out of the histidine decarboxylase gene) minimizes also the level of ACTH [52]. The immune cells not only produce ACTH, but they also have specific ACTH receptors [52]. As it was mentioned - lier, the cells also have CRH receptors and the binding of CRH stimulates ACTH production [53]. In contrast to the identical capacities of pituitary and immune cell-derived ACTH it is uncertain that its amount or quality is enough for stimulate adrenal steroidogenesis. Some data support this, other not [54–56]. Similarly, the role of ACTH production by the immune cells is not so clear, as it is in the case of endor- phin.

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The thyrotropin group (TRH, TSH, T3)

After the recognition of ACTH and endorphin in immune cells, the pres- ence of another pituitary hormone has been studied and found. This hormone is the thyrotropin (TSH), which is produced by lymphocytes [2] in which the TSH beta subunit gene was also demonstrated [57]. This supported the theory of Blalock and his team on the presence of pituitary hormones in immune cells, in general. However, not only the pituitary hormones are produced by the immune cells, but numerous other hormones and among them, the target hormone of TSH, triiodothyronine (T3) [58]. This hormone was present in all types of immune cells, in lymphocvytes, the -, group and in mast cells [58] of the rat as well as in man [59]. Immune-cell T3 was demonstrated already in the newborns [60]. The anti-thyroid , thiamazole strongly influenced the T3 content [61], in the immune cells, too. The thyroxine-T3 conversion, which is characteristic to the pituitary gland also can be observed in the lymphocytes [62]. T3 strongly influences the immune functions [63, 64]. T3 receptors belong to the receptor superfamily, and dendritic cells, which activate naïve T-cells, have these receptors [65]. However, T3 production by the immune cells is regulated by TSH [66], which is also produced by these cells. Thyrotropin releas- ing hormone (TRH) regulates TSH production [67], and immune cells have TRH receptors. So, there is a TRH-TSH-T3 chain, which modulates different immune functions [68, 69]. Although in our present knowledge the TRH-TSH-T3 axis has an important ïrole in the regulation of immune functions, other hormones can also influence this effect. For example the synthetic hormone, coun- teracts with the effect of T3 on dendritic cells [70]. Stress, caused by any factors deeply influences the T3 content (production) of the immune cells. In acute stress condition the lymphocytes are the most sensi- tive [71], for increasing the T3 level, however, in chronically stressed animals the T3 level is reduced (together with impaired ), which can be restored by the replacement of the hormone [72]. Stress at weaning had a prolonged increas- ing effect to T3 production, while stress in adults decreased T3 in the immune cells of peritoneal fluid, and an increasing effect was observed in blood immune cells [73]. The above-mentioned facts show that the TRH-TSH-T3 axis play a signifi- cant role in the immune regulation However, it is not cleared what other, not im- mune effects of the immune-produced hormones can be found.

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Somatotropic hormone (, GH)

GH is produced mainly by the pituitary gland under the regulation of the hypothalamus, influencing growth processes, as and having a general anabolic effect. However, immune cells also produce it, and it has important func- tion in the regulation of immune functions by an autocrine or paracrine way [74]. The hormone is synthesized and secreted by lymphocyte cell lines as well as pe- ripheral (blood) lymphocytes [75, 76]. The structure and bioactivity of immune cell-derived GH is identical with the hormone, produced by the pituitary gland. The immune-derived hormone has three isoforms (100, 65 and 48 kDa) and the high molecular weight isoform is localized mainly in the cytoplasm, while the low molecular weight isoforms primarily in the nucleus [77]. can induce GH se- cretion from lymphocytes [78]. The immune cells have GH-receptors [79], and also can produce growth hormone releasing hormone (GHRH), which has similar bioactivity to nerve cell-derived GHRH [80]. Each type of mononuclear immune cells (monocytes, B and T cells) synthesize GHRH. However, in aging men and women a decrease in the number of GHRH-producing immune cells was observed [81]. T-cells’ pro- duction of the hormone was more (5–7-fold) expressed. Chronic stress also re- duces the level of immune-derived GHRH [82], similar to aging [83]. GH stimu- lated the proliferation of immune cells, primarily T-lymphocytes [84–86]. The im- mune cells also have GH and GHRH receptors [84].

Prolactin

Prolactin is a pituitary hormone, having protein character. Its first recog- nized role was the stimulation of the growth of during pregnancy and regulation of milk production. However, it has a role also in the immune sys- tem. Not only the lactotropic cells of the pituitary produce and secrete prolactin, but also the mononuclear immune cells [87]. The immune cells have also prolactin receptors [88] and by this, there is a possibility of autocrine, paracrine and endo- crine regulation and influence to the proliferation of these cells [89]. The hormone is produced not only by the cells of healthy animals and men, but in such sick- nesses, as systemic erythematosus (SLE) and other autoimmune , however, not all of them require its participation [90]. It is supposed that the hor- mone has important role in these diseases [91–94] what is demonstrated by

Acta Microbiologica et Immunologica Hungarica 61, 2014 HORMONES IN THE IMMUNE SYSTEM 247 hyperprolactinemia in SLE patients and more prolactin production by T-lympho- cytes in these cases [95]. Prolactin has an immunostimulatory effect, influencing first of all the func- tion of the B-lymphocytes [94]. It acts as a as it is able to bind not only to the prolactin receptors of the immune cells, but also to their cytokine receptors [84]. Prolactin is able to restore the lost immunocompetence [96].

Melatonin

The pineal body is a regulator of the developing [97] and functioning [98] immune system. Its such effect is manifested primarily by its product, melatonin. However, immune cells, mainly lymphocytes are also producing melatonin and their hormone is participating in autocrine, paracrine and endocrine regulation of the immunity [99–101]. This is helped by the presence of melatonin receptors on the plasma membrane and in the nucleus of these cells [102, 103]. Though the presence of and effects on lymphocytes are the most well known, other cells of the immune system as monocytes-macrophages, dendritic cells, , , , mast cells and NK cells are involved in the hormone production and hormone reception. [104]. The -specific T-cell response is influenced by it [105], and it stimulates the production of NK cells and CD4+ cells, while inhibits that of CD8+ cells. It increases the transfor- mation of progenitor cells to granulocytes and macrophages. Various cytokines’ production is also enhanced by it [106]. During aging the melatonin, produced by the immune cells helps to supplement melatonin which is lost by the deterioration of pineal body [107]. Melatonin has a role in the defense against and the lo- cal presence of melatonin secreted by the immune cells could have a role in it [103]. Immune cell-derived melatonin could have a role in the defense against the effect of free radicals [108].

Other hormones in the immune cells

As it was mentioned, T3 is present in the immune cells, regulated by TRH and TSH. However, other non-brain hormones are also synthesized, mainly bio- genic amines. Histamine, serotonin and epinephrine can be found (in rat and hu- man), however, in granulocytes serotonin and epinephrine were not found.

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Monocytes contain more histamine and epinephrine than lymphocytes and granu- locytes contain (in man) twice as much histamine than monocytes and three times as much as lymphocytes [112]. The experiments with non-brain hormones call at- tention to the possibility of a hormonal network inside the immune system [113], as hormones in an extremely low concentration can influence the hormone pro- duction of each other. The hormone content of the immune cells shows gender de- pendence, with the advantage of females [50]. Catecholamines are also present in the immune cells, e.g. [114]. Lymphocyte-derived dopamine by an autocrine way regulates lymphocyte growth and differentiation, which means that dopamine receptors are also present in the membrane of these cells [115]. Dendritic cells, Treg cells, granulocytes and macrophages also synthesize and secrete dopamine, influencing Th immune re- sponses [116]. Lymphocytes produce chorionic gonadotropin [117]. Mast cells synthesize a gonadotropin-releasing hormone (GnRH)-like molecule [118] and thymocytes as well, as lymphocytes produce luteinizing hormone releasing hormone (LHRH) with similar immune-activity and bioactivity as the brain-derived hor- mone [119, 120]. Renin [121], vasoactive intestinal peptide [122, 123], angiotensin II [124] also can be found and secreted by immune cells. Cryptic insulin receptors are pres- ent in the plasma membrane [125], however, insulin itself was not found.

Immune cells and hormones during pregnancy

Pregnancy is a special state, when the female organism has to tolerate the half-foreign embryo. This requires the presence of partly transformed immune cells [109] and their hormonal activity. NK cells and monocytes synthesize and secrete chorion godotropin (hCG), which helps to sustain the corpus luteum at the early gestation and participates in the (105). Lymphocytes (Tregs?) accumulate around the developing embryo and manifest re- ceptors, which bind progesterone and under the effect of it produce a mediator (PIBF) which inhibits NK activity, which is dangerous for the [110]. The uterine natural killer (uNK) cells are transformed from peripheral blood NK cells and are accumulated in the . These cells help the development of placental vessels [111]. The transformation of the cells, is a consequence of the reaction to sexual .

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Conclusions

The immune system is composed from cells, which have a recognition ca- pacity (self – non-self) and ability to destroy the non-self, which could harm the organism. All of the cell-types, which have these characteristics are registered as members of the immune system and are studied for such indexes which serve this function. If we would not know, that these cells belong to the immune system and handle them as virgin (originally functionless) cells and found that they produce endocrine substances and react to them, they could be registered as members of the endocrine system. Later it would be observed their self–non-self recognition capacity and would be told that some members of the endocrine system have also these capacities. This means that the priority of observations determines the func- tional arrangement. However, the immune system’s immunological function is al- most completely mapped, while the immune-endocrine system is disordered and accidental. Practically all of the hormones, which were searched at all, were found in it and the same is in the case of hormone receptors. This allows the supposition that these cells are polyproducers from this point of view, similarly to the phylo- genetically ancient cells. At the low level of phylogeny, in the unicellular , as in Tetra- hymena also can be found all of the mammalian hormones (except steroids, which were also not found in immune cells) which are synthesized, stored and secreted [126]. In addition, the cells have binding sites for these hormones, which are strengthening to real receptors after the first encounter with the hormone (hor- monal imprinting) [127, 128] and very low concentrations are needed for the se- lective recognition of a signal molecule. It seems to be likely that during the phy- logeny unicells are collected to form multicells, where later the specification of cell groups was taking place. This specification resulted in the appearance of en- docrine organs in which the earlier polyproducer cells’ function narrowed to uniproducer one. This can explain why insulin can be found in practically each mammalian cell types studied [129, 130] and why this function concentrated in the Langerhans islets. Considering these thoughts it is not known whether the im- mune-hormonal system is a real one or a consequence of the work by diligent re- searchers for whom the easily separable immune cells gave better objects, than other ones. However, the enormous amount of hormone-producing immune cells – which exceeds in weight that of brain or liver –, and the completeness of hor- mone-receptor system in them, makes believable that there is an immune-endo- crine system really. From this point of view, the immune-endocrine system is a mass of cells which retain their ancient capacities, while the endocrine glands are

Acta Microbiologica et Immunologica Hungarica 61, 2014 250 CSABA accumulations of cells, which specified for the interest of a more sophisticated production of hormones. Exactly, it is not known presently, whether the hormone production of immune cells is influenced by feed-back, while it has a decisive role in the regulation of hormone secretion by endocrine glands. Considering the idea, mentioned above, the feed-back in the immune-endocrine system seems not to be likely, as it is also absent in the case of phylogenetically ancient cells [131, 132]. If we accept that the participation of immune cells in the endocrine network is specific one – and we do it – the question arises, why is it necessary, if there is a “professional” glandular endocrine system? The answer seems to be complex. As it was mentioned previously, immune cells are polyproducers of hor- mones. This means that any hormones can be synthesized and secreted by them under the effect of adequate stimuli. In addition, immune cells are mobile, which means that they can appear in any places of the organism, under the effect of local factors, which attract them. This is, e.g. in case of inflammation. Inflammation at- tracts immune cells, which are participating in the defense against it, however, at the same time, secreting endorphin which calms the pain caused by the inflamma- tory process. This is the most intensively studied immune-endocrine target phe- nomenon, however, many others could be unknown at present. The secretion of hormones by endocrine glands into the blood circulation is partly waster, partly dangerous, as each targets are influenced, not only that, for which the hormonal stimulation (inhibition) is needed. The local – packed – trans- port of the hormone [133] is economical and does not contaminate timely not-needed targets. The local inducer – a factor of the target object or a trop-hor- mone secreted by other immune cells, or by the target-hormone synthesizing cell itself (autocriny) commands the secretion. However, there is a possibility of trans- port of cell-stored hormones – without new synthesis – and secretion of them to the site of need. The glandular endocrine system would be the main regulator, maintaining the chemical (neuroendocrine) balance, and the hormone producer during general stress states, while the immune-endocrine system would solve the tiny local problems and supplements the solution of the problems of glandular sys- tem. However, this latter is not clear. There are no experiments or observations which could show that the shortfall or deficiency of any endocrine gland could be supplemented by immune endocrine products. This seems to be very interesting, as the hormones produced by the immune cells are identical in structure, antige- nicity and bioactivity with the productions of glandular cells, and considering the amount of immune cells theoretically could be more, than the products of the en- docrine glands. This supports the theory that the immune cell-derived hormones

Acta Microbiologica et Immunologica Hungarica 61, 2014 HORMONES IN THE IMMUNE SYSTEM 251 are serving for influencing local processes, however, it is not explained why only them. The immune-endocrine system seems to be more ancient than the glandular one. This is supported by the hormone-polyproduction, the diversity of cells which are able to produce the same hormones and by the fact that synthesis of ste- roid hormones was not found in immune cells, although and its synthetic products drastically influence immunity. Only peptide and type hor- mones was found and also receptors for them. In addition, as it was mentioned, unicellulars (Tetrahymena) have receptors of the hormones of higher ranked ani- mals, which were searched at all, what means that they are not only polyproducers of, but polyreceivers for hormones, at the same time. The same situation is in the case of immune cells. This also shows that these cells conserved the ancient prop- erties. It is interesting that the hormone producing immune cells have a meso- dermal origin, while the glandular system is meso-ecto and endodermal. The higher regulation of the glandular endocrine system is completely ectodermal. There is a theoretical possibility that in the primitive multicellulars the ancestors of immune cells had the role of defense and endocrine character alike, and this is retained in the hormonal activity of immune cells. The and the glandular endocrine system are now called to neuroendocrine system. In this system the neural part can recognize its environment and can memorize it. The endocrine part is the chemical executor which works under the influence of the neural part. In the immune-endocrine sys- tem this two parts are together, in the same cells. The cells can recognize (this is one of the main functions of immunity) and store the information (memory) and can execute the commands provoked by the recognition. Though the cells of the systems have different origins, forms and functions, the two systems have a func- tional similarity. They together are responsible for the homeostasis and functional integrity of the organism and in this process their similar functions are very impor- tant. However, the advantage of the more developed neuroendocrine system is the more exact, fast recognition and the general effects of the executor (hormones) and that is in the immune-endocrine system the locality and mobility. As in the immune-endocrine system the hormones are not produced by “professional” endocrine cells, but immune cells, mostly – except in the case of endorphin and melatonin – [134], the studies were directed on the effects to immu- nity. As it was listed above, there were many effects demonstrated, however, it is not sure at all that these are the most important local effects of the hormones se- creted by the immune cells. It is important to know that many non-hormonal

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– physiological or non-physiological – factors are influencing immunity and the hormones are some of them. The specific effect of hormones – except melatonin – to the immune system seems to be dubious. At the same time in some cases the other – non-immune – effects of immune cell-derived hormones are certain, as it is in the case of endorphin. There is a possibility that the meaning of a locally produced and in a mini- mal-dose secreted hormone is different, from the same hormone, circulating in the blood in a high quantity. Also, possible that endorphin is a pain-killer also in other, non-inflammatory cases, however, inflammation was the simplest model to study the effect. It is no way that T3 can locally influence the metabolism of stressed cells saving them by it, without disturbing other cells of the organism, etc. There would be such cases, when the role of the immune endocrine system surpasses that of neuroendocrine one. For example during early pregnancy, when it could have had a very important role in the tolerance to the embryo during im- plantation to the . Although there are some data on this embryo- nal--saving immunological role of uNK and other cells, there are only scarce data on the non-immunological local role of these hormones [135–137].

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