The Hypothalamuspituitarythyroid Axis

Thyroid Factor

The Natural Thyroid Diet

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4.1. Thyrotropin releasing hormone (TRH)

B and T lymphocytes have receptors for TRH [145], TRH treatment of rats significantly increased the proliferative response of spleen cells to Con-A [147]. TRH stimulated T cell development in the gut but not in the spleen [148]. In man TRH elevated serum IFN-y levels [150]. Repeated TRH administration in critical illness resulted in a repetitive increase of TSH, PRL, GH, thyroxin (T4), and triiodothyronin (T3), without increasing reverse T3 [151].

4.2. Thyroid stimulating hormone (TSH)

TSH receptors (TSHR) are present in B and T cells, NK cells, monocytes and at high levels in dendritic cells (DC). TSHR are not detectable on foetal and neonatal immune cells. TSH significantly stimulated IL-2 and IL-12, IL-1 [3 responses and enhanced the phagocytic activity of DCs from adult animals, enhanced the proliferative response of murine spleen cells to IL-2, significantly increased IL-2 induced NK cell cytotoxicity and enhanced the expression of MHC-II by human thyroid epithelial cells [149,152-156], In bone marrow cells IL-6, IFN(3, TNFa, TNF|3, TGF|32, and lymphotoxin-|3 responses were reproducibly induced by TSH [158], Lymphocytes and monocytes synthesize TSH [149,158],

4.3. Thyroxin (T4) and Triiodothyronin (T3)

Lymphocytes and monocytes express nuclear receptors for both T3 and T4. Human lymphocytes convert T4 to biologically active T3. T3 regulates sodium exchange and glucose uptake in lymphocytes, stimulates thymus growth and hormone production, and promotes erythroid burst forming clones and B cell maturation in the bone marrow. In animals thyroid hormones have diverse effects on lymphocyte proliferation, antibody formation to various antigens, and on various cell mediated reactions, including NK cell activity. Thyroid deficiency was usually, but not always, associated with immune deficiency, which could be restored by treatment with T3. Hypothyroidism in man was associated with immunodeficiency. The supplemental treatment of normal animals with T3 yielded mostly negative results [36,158-166],

T4 inhibited the development of TCRap, CD8 in intestinal intraepithelial lymphocytes (IEL) in 6-8 week old euthymic mice [167], The NK cell number and/or cytolytic activity of healthy subjects > 90 years old correlated positively with serum levels of vitamin D, while T3, FT4, i-PTH hormones and lean body mass were correlated only with NK cell number [168],

Dendritic cells inhibited the proliferation of rat thyroid follicles, which was mediated by IL-1(3 [169], IL-1 in moderate to high concentrations inhibited thyroid cell (TEC) function, which was supported by TNF and IFNy. IL-1 induced the release of NO and cGMP, inhibited the adenylate cyclase mediated pathways and stimulated the guanylate cyclase mediated pathways in TEC. IL-1 receptor antagonist counteracted these IL-1 effects [170], The binding of thyroid hormone receptors to the DR4 thyroid hormone responsive element was markedly decreased in the spleens of rats with adjuvant arthritis (AA) or with AA + adrenalectomy [171]. Thyroid hormone deficient mouse strains showed a defective primary B cell development. Other haematopoietic cell lineages and mature B lymphocytes were normal LI72],

5. NERVE GROWTH FACTOR, LEPTIN AND NEUROPEPTIDES

Nerve growth factor (NGF) shares tyrosine kinase receptors with other neurotropic factors that belong to the TNF receptor superfamily and are present in lymphoid cells and cells of the nervous system. NGF stimulates mast cells, haemopoietic colonies and neutrophilic leukocytes and locally exerts a proinflammatory effect. However, systematically applied NGF suppresses inflammation. Lymphocyte-derived NGF protects the nervous system and other tissues from inflammatory damage [173,174],

Leptin (LEP) is adipocyte-derived. It belongs to the GLH cytokine family and signals by a class I cytokine receptor. LEP regulates energy metabolism, reproductive function, lymphocyte development and function, and it up-regulates phagocytosis and proinflammatory cytokines. LEP stimulates the production of IL-Ira, which protected mice against LPS toxicity. In murine glial cells LEP stimulated IL-1 (3, it promoted wound healing and angiogenesis. During the acute phase response (APR), LEP increased rapidly in response to elevated TNF levels. LEP contributes significantly to survival in sepsis by moderating glucocorticoid and IL-6 production, stimulating IL-Ira and potentiating the immune response [175-184].

Arginine vasopressin (AVP) type receptors are present on human PBMC. AVP stimulated the production of prostaglandin E2 (PGE2) by human mononuclear phagocytes, and the production of (3END by human PBMC. AVP is antipyretic and it attenuates fever after central administration [6,185,186],

Substance P (SP) is produced in both the nervous- and in the immune systems. SP is a major mediator of neurogenic inflammation. SP induces mast cell discharge, increases capillary permeability and smooth muscle contraction, stimulates immune phenomena, bone marrow cytokines and the formation of granuloma tissue, increases Fey and e receptors and decreases C3b receptors on eosinophils, releases TNFa from macrophages and modifies macrophage function during stress. In polymorphonuclear leukocytes SP stimulated the respiratory burst and chemotactic and phagocytic activities [187-194], SP increased the release of PGE2 and collagenase from rheumatoid synoviocytes [195] and PGA and thromboxane B2 from astrocytes [196], SP induced IL-3 and GM-CSF secretion by bone marrow cells, which was mediated by the stimulation of IL-1 and IL-6 [197], SP activated platelet cytotoxicity against Shistosoma mansoni larvae and its receptor was necessary for the normal granulomatous response [198],

Calcitonin gene related peptide (CGRP) stimulates mast cell discharge and inflammation, inhibits antigen presentation, lymphocyte proliferation, IL-2 production, mRNA synthesis for TNFa, -(3 and IFN-y and suppresses IFN-y induced H202 production by human monocytes. T lymphocytes synthesize CGRP [ 199-201 ].

Somatostatin (SOM) is an antagonist of SP and inhibits inflammatory and immune reactions. SOM is beneficial in models of autoimmune disease and chronic inflammation. Lymphocyte proliferation, endotoxin induced leukocytosis, IgA secretion, and IFNy production are inhibited by SOM. Its effect on antibody dependent cytotoxicity is variable. SOM exerts a regulatory influence on macrophages [ 190,191,202-204],

Vasoactive intestinal peptide (VIP) receptors are present on monocytes and lymphocytes. VIP stimulated macrophage chemotaxis and inhibited lymphocyte chemotaxis through the activation of adenylate cyclase [205], it enhanced phagocytosis by mouse peritoneal macrophages [206], Immunoreactive VIP was detected in rat thymus, spleen and lymph nodes in both lymphoid and non-lymphoid cells [207].

Pituitary adenylate cyclase activating peptide (PACAP) and VIP inhibited the nuclear translocation of NFkB in stimulated macrophages. This antagonised the effect of IFN-y and down-regulated the inflammatory response. The production of TGF-(3l, IL-4, -6, -12, TNF-a and NO were inhibited by both peptides [208-213], IL-6 production was enhanced by VIP/PACAP in unstimulated macrophages [214],

Various immune cells express (3-type adrenergic receptors. Beta-adrenergic agents inhibit allergic and asthmatic reactions and various immune phenomena. Acetylcholine and cholinergic agents, by acting on muscarinic receptors, enhance immune phenomena, including the release of histamine and other mediators from mast cells. Allergic patients show an increased sensitivity to cholinergic stimulation (214).

6. STEROID HORMONES 6.1. Glucocorticoids (GC)

Leukocytes express GC receptors (GR) [215,216]. GR are bound to heat shock protein 90 (HSP90) in the cytoplasm and function as nuclear transcription factors. GR modulate the transcription factors API, iKBa, and the cAMP-responsive element binding protein (CREB) [217— 220]. Membrane GR initiate apoptosis [221]. Macrophage migration inhibitory factor (MIF) counter-acts GC action [222]. Lipocortin 1 is a GC-induced protein, which inhibits neurogenic inflammation. [223,224]. Cytokines that activate AP-1 may induce steroid resistance [225,226]. The thymic epithelium synthesizes GC, which inhibits T cell antigen receptor (TCR)-mediated apoptosis [227-229], GC induce thymus involution [36,230,231], Cytokines prevent their own toxicity by stimulating GC production, and by modifying target cell sensitivity for GC counter-regulatory action [232],

In the monocyte-macrophage lineage, metabolism, chemotaxis, phagocytosis, cytotoxic reactions, antigen presentation, IL-1, IL-lra, IL-6 secretion and the ability to respond to lym-phokines are inhibited by GC. In macrophages GC suppressed the production of collagenase, elastase, plasminogen activated TNFa, superoxide and NO [36,233-235],

GC increased HLA antigen and IFNy receptor expression [236,237], and potentiated the induction of Fc-y receptors in human monocytes by IFNy [238], Low concentrations of GC induced MIF production by macrophages. MIF could override the GC-mediated inhibition of cytokine secretion by LPS activated monocytes and antagonized the protective effect of GC in lethal endotoxemia [239],

Dexamethasone (DEX) inhibited the IL-12-induced IFNy secretion and IFN regulatory factor-1 expression in NK and T cells [240], GC inhibited NK cell-mediated cytotoxicity and ADCC, and this effect was potentiated by PGE2 and abrogated by IFN-y or IL-2 [36,241 ].

GC have a powerful anti-inflammatory effect, including action against neurogenic inflammation. This is the result of GC action on cytokine and other mediator secretion, inhibition of leukocyte priming, reduction of vascular permeability, and synergism with other anti-inflammatory mediators, such as catecholamines, (3END and a-MSH [223,242-244]. The general hypersensitivity to GC is eliminated at the site of inflammation by locally produced cytokines [245],

GC induced mast cell destruction in rats and depleted cutaneous mast cells in man [246], GC inhibited mediator release from mast cells and basophilic leukocytes [247], Neonatal GC treatment reduced the corticosterone response to LPS in adult rats; LPS-stimulated macrophages of such rats produced less TNF-a and IL-1 (3 and splenocytes showed increased mRNA levels for IFNy and TNF-(3 [248],

The GC response peaked 36 hours after murine cytomegalovirus (MCMV) infection, coincident with elevated blood levels of IL-12, IFN-y, TNF, and IL-6, and was dependent on IL-6 for maximal release. Adrenalectomised (ADX) mice were more susceptible than controls to MCMV-induced lethality, which was mediated by TNF and could be reversed by GC replacement. Lack of endogenous GC resulted in increased IL-12, IFN-y, TNF, and IL-6 production as well as in mRNA expression for IL-1 a and IL-1 (3. [249],

6.2. Aldosterone

Aldosterone, which is a GR-I agonist, significantly reduced the number of lymphocytes and monocytes and, unlike RU48362, also decreased the number of neutrophils. T helper cells and NK cells were decreased by aldosterone. Corticosterone at physiological doses behaved like a GR-II agonist in these experiments. The GR-II agonist RU48362 decreased T and B and NK cells to a very low absolute level in young adult rats. [250].

6.3. Sex hormones 6.3.1. Gonadotropins

Pyrogenic cytokines, especially IL-1 (3, are significantly influenced by exogenous gonadal steroids and gonadotropins. [251]. IL-1 (3, generated in the central nervous system (CNS) during inflammation, upregulates opioids and tachykinins in the hypothalamus which cause the sup pression of hypothalamic luteinizing hormone releasing hormone (LHRH) and pituitary luteinizing hormone (LH) release [252].

6.3.2. Sex hormone receptors and signalling

Estrogen (ER) and androgen receptors (AR) are present in lymphoid tissues. The classical estrogen receptor (ERa) is detectable in lymphoid tissue, however, ER(3 is more abundant in lymphoid cells. Progesterone (PS) also acts through GC receptors in addition to its own specific receptors (PR). At high concentrations estrogens and androgens also act on GR [253-256]. Membrane bound steroid receptors, which include the polyglycoprotein (PGP) pump also exist. [257]. ER binds to estrogen response elements (ERE) in target genes, recruits a coactivator complex called CBP-pl60 that mediates the stimulation of transcription, and also activates AP-1 sites that increases the activity of Jun/Fos [258,259]. ER interacts directly with the transcription factors NF-IL6 and NFkB, and inhibits their binding to DNA, which is likely to be the molecular basis for repression of IL-6 gene expression by estrogens. Unlike estrogens, the anti-estrogen, tamoxifen (TX) does not inhibit the induction of the IL-6 promoter [260].

Three dimeric species of PR, namely A/A, A/B, and B/B may be formed and bind to progesterone response elements (PRE) and subsequently regulate transcription. Receptor dimerization is obligatory for binding to PRE, but it is not sufficient to activate transcription without the hormone. In pure heterodimers, A receptors are dominant negative inhibitors of B receptors [261-263],

6.3.3. Estrogens

Estradiol (E2) causes thymic involution, suppresses bone marrow function, cell-mediated immune reactions, including the helper, suppressor and effector functions of T lymphocytes. Natural killer cells, neutrophils and mast cell degranulation are also inhibited by E2. Phagocytosis, antibody production and some autoimmune diseases of animals are enhanced by E2 [36,264,265],

In rat alveolar macrophages E2 and PS inhibited NO production [266], In mice E2 inhibited the homing and activation of inflammatory cells and their production of TNFa and IFNy [267], and reduced NK cell-mediated cytotoxicity [268]. In ovariectomized rhesus monkeys nine months after E2 replacement killer cell activity was reduced [269], E2 modulated both pro- and anti-inflammatory cytokine activities [270], In women, ovarian hyperstimulation led to neutrophil activation, which correlated with the degree of luteinization. Neutrophil L-selectin expression negatively correlated with serum progesterone levels [271].

6.3.3.1. Immunomodulation by antiestrogens. The non-steroidal antiestrogen, TX, has an antiproliferative effect on lymphocytes, interferes with the stimulatory effect of E2 on phagocytosis, inhibits giant cell formation by monocytes and blocks H,0, production by human neutrophils. TX enhanced the LPS induced production of TNFa by human monocytes and by rat peritoneal cells [257,272-274],

TX and toremifene (TO) decrease serum PRL, GH and IGF-I levels, influence the expression of hormone receptors and their binding proteins, which also affect the immune system. TX-induced immunosuppression in rats could be reversed by treatment with either GH or PRL. TX also antagonized the stimulatory effect of PRL on lymphoid cells [257,275]. TX antagonized the inhibitory effect of E2 on NK cells. NK, LAK and CTL effector cells maintained their cytolytic activity after treatment with 1 ^M TX or 5 uM TO, which are commonly achievable during cancer therapy. In murine tumour systems both TX and TO enhanced the immunotherapy (e.g., by NK, LAK or CTL effectors) of ERa negative tumours, which led to the cure and long-term survival of a significant proportion (50-75%) of animals with lethal cancer [276-282].

Antiestrogens enhanced the cytotoxic effect of anti-Fas monoclonal antibody in the majority of human ovarian carcinoma cells so examined. In Fas negative K562 target cells the NK mediated perforin/granzyme pathway of immune cytolysis was also enhanced [274,283,284].

6.4. Androgens

Human lymphocytes metabolize sex hormones and are capable of synthesizing androgens [285]. In general, testosterone (TS) suppresses immune reactions. The development of the bursa of Fabricius is prevented by TS in chicken embryos. TS has been proposed to selectively favour the differentiation of suppressor T lymphocytes in the thymus [36,286]. MHC-linked genes influence the effect of androgens on the immune system [287]. Androgens stimulate haemopoiesis [288]. In the thymus TS is converted to E2 by aromatase and E2 is a powerful inducer of thymic involution [289]. Dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA) restored the capacity of T cells to produce IL-2, IL-4 and IFN-y in aged mice to the levels of young animals [290],

TS inhibited NO release and stimulated the release of reactive oxygen intermediates from rat peritoneal macrophages [233], inhibited inducible NO synthesis in the RAW 264.7 murine macrophage cell line [291]. In guinea pigs, androgens (TS, DHT and mesterolone) impaired the clearance of IgG-coated cells by decreasing splenic macrophage FcyR expression. Antiandro-gens (flutamide, nilutamide, cyproterone acetate, spironolactone, and finasteride) counteracted the inhibitory effects of androgens [292].

In women, androgens slightly decreased free urinary Cortisol levels and enhanced the mitogen-induced IFNy/IL-4 ratio and TNFa production. [293]. Bioactive TGI-j^ fell to approximately 50% after castration of male mice and was normalized 1 week after TS treatment. TS modulated the production of TGF-p by thymocytes [294]. In male mice DHT significantly decreased the releases of IL-ip and IL-6 by splenic and peritoneal macrophages after trauma-haemorrhage. DHT-treated animals exhibited increased IL-10 and Kupffer cell IL-6 release. Estrogen prevented this immunodepression in castrated male mice [295,296].

Both pregnenolone (PREG) and DHEA are metabolized by the spleen and the derivatives, which include testosterone, DHT, androstenediol (AED) and androstenetriol (AET), are much more potent immunoregulators than DHEA itself. [297], Human monocytes express receptors for DHEA. In monocytes DHEA enhanced the induction of cytotoxicity, IL-1 secretion, reactive nitrogen intermediate release, and the expression of complement receptor-1 and TNFa protein [298],

Plasma levels of DHEA-S, AED and TS are suppressed in chronically ill patients and in those treated with DEX. This is corrected by ACTH [299], DHEA-S is depressed in postmenopausal women with rheumatoid arthritis [300], In postmenopausal women treated with physiologic doses of DHEA for 3 weeks, CD4+ T cells were decreased and CD8+/CD56+ (natural killer) cells increased. T cell mitogenic and IL-6 responses were inhibited, whereas NK cell cytotoxicity was dramatically increased [301],

6.5. Progesterone (PS)

PS is immunosuppressive. It suppressed lymphocyte proliferation [302] and the anti-Candida activity of neutrophils from mice [303], PS significantly inhibited nitrite release and stimulated the release of reactive oxygen intermediates [304] and stimulated TNF release from rat peritoneal macrophages [234], Human PBMC, stimulated with LPS, produced less IL-1 upon exposure to PS, whereas IL-6 secretion was not altered. However, PS failed to inhibit IL-1 secretion by PBMC from male donors with rheumatoid arthritis [305],

PS protects the foetus against maternal immune reactions [306,307] and lymphocyte sensitivity to PS is increased during pregnancy, due to the expression of PR by y8 T lymphocytes in response to foetal antigens, leading to the production of a progesterone-induced blocking factor (PIBF). PIBF acts on the phospholipase A2 enzyme, interferes with arachidonic acid metabolism, induces a Th2 biased immune response, and exerts an anti-abortive effect by controlling NK activity [308], PS treatment of mice suppressed glucocorticoid-induced thymocyte apopto-sis [309] and decreased host resistance against viral and fungal infections [310,311],

6.6. 1,25-Dihydroxivitamin-D3 (VD3)

The VD3 precursor, cholecalciferol, is present in the diet and induced in the skin by UV radiation. 25-Hydroxy vitamin D3 is generated in the liver, which is processed further by 1-hydroxylase in the kidney, in monocyte/macrophages, in keratinocytes, bone marrow, placenta, glia cells and pneumocytes [312-314],

The VD3 receptor (VDR) interacts with VD3 responsive elements (VDRE) on DNA and also with the retinoic X receptor (RXR). Stimulation and inhibition are both possible through VDRE. Protein kinase C is involved in VDR mediated signalling and VD3 regulates the DNA binding subunit of NFkB. Monocyte/macrophages, activated T lymphocytes, and bone marrow cells express VDR [312-315], The GM-CSF enhancer is transcriptionally repressed [316] and the IFNy promoter is down-regulated by VD3. [317],

VD3 is a potent anti-proliferative and pro-differentiation mediator for macrophages, lymphocytes and other cells [318], In monocytes/macrophages, adherence, chemotaxis, phagocytosis, cytotoxicity, H202, oxygen radicals, and HSP production are stimulated by VD3. Antigen presentation, the production of IL-1, -2, -6, -12, TNFa, IFN-y and the function of Th-1 cells are inhibited. Suppressor T cell function, B cell proliferation and Ig secretion are inhibited. Natural killer cell cytotoxicity is stimulated [312,313],

The NK cell number and/or cytolytic activity of healthy subjects greater than 90 years old was positively associated with serum levels of vitamin D, while T3, FT4, i-PTH hormones and lean body mass were associated only with NK cell number [168],

The regulation by neurohormonal regulatory factors of natural immunity is summarized in Table I.

7. IMMUNOCONVERSION IN THE ACUTE PHASE RESPONSE 7.1. Introduction

The healing power of fever has been recognised in ancient Egypt, Greece the Roman and Persian empires and fever therapy was practised during the first half of the 19lh century [319] using whole

Table I Major hormonal and neural regulators of natural immunity.

Hormone NK yöT CD.TB/NAb CTK PHAG CTX APP 1NFL

Mediator

Hormone NK yöT CD.TB/NAb CTK PHAG CTX APP 1NFL

Mediator

HPT axis

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