Dr.Flory Revnic*,Dr. Bogdan Paltineanu**,Dr.Catalina Pena*,Dr.Speranta Prada*,Dr.Cristian Romeo Revnic***
*NIGG”Ana Aslan”
**UMF Tg.Mures
***Ambroise Pare`Hospital,University Pierre&Marie Currie Paris VI, France
Part one
Rezumat
Aceasta lucrare este o trecere in revista a datelor din literatura de specialitate privind legatura dintre axa hipotalamo-hipofizo-corticosuprarenala si inflamatia mediata imun
Este cunoscut faptul ca sistemul imun este reglat de catre sistemul nervos central (CNS) prin doua mecanisme majore:1). Raspunsul hormonal la stres si producerea de glucocorticoizi si 2)Sistemul nervos autonom care elibereaza noradrenalina. De asemenea, (CNS) regleaza sistemul imun local prin intermediul nervilor periferici prin eliberarea de neuropeptide precum substanta P si prin producerea locala de corticotropina. Este discutat mecanismul prin care glucocorticoizii isi exercita efectul asupra inflamatiei mediate imun.
Abstract
This is a review of the literature data on the relationship between (HPA) axis and immunomediated infamation. It is well known that the immune system is regulated by the central nervous system(CNS) through two major mechanisms: 1)the hormonal stress response and the production of glucocorticoids, and 2) the autonomic nervous system with the release of noradrenalin. Also, (CNS) can regulate the immune system locally via the peripheral nerves with release of neuropeptides such as substance P and locally produced corticotrophin-releasing hormone. This paper discusses the mechanism regarding glucocorticoids effect on immunomediated inflammation.
Introduction
Hipotalamo-hypophyseal-adrenal (HPA) axis is the main regulator of the glucocorticoid effect on the immune system [1-4]. It interacts with the immune system,sensing inflammatory signals and modulating the activity of this system primarily via its end product, glucocorticoids. Three cytokines – TNF-α, IL-1 and IL-6 – account for most of the HPA axis-stimulating activity in plasma. Systemic IL-6 concentrations also increase during stress unrelated to inflammation, presumably stimulated by catecholamines acting through β2- adrenergic receptors.
The release of CRH from intrahypothalamic neurons is the first step in HPA axis activation. CRH, travel from the hypothalamus via the hypophyseal–portal
blood vessels to the anterior pituitary gland where it acts via specific receptors to trigger the release of the adrenocorticotrophic hormone (corticotrophin, ACTH) from specific ACTH-14 producing cells into the systemic circulation. ACTH in turn acts on the adrenal cortex via melanocortin receptors to initiate the synthesis of cortisol, which is released immediately into the systemic circulation by diffusion.
The magnitude of the HPA response to incoming stimuli is tempered by the glucocorticoids which act at the levels of the pituitary gland and hypothalamus to suppress the synthesis and release of ACTH and CRH.
The molecular mechanisms by which the glucocorticoids exert their negative feedback effects are complex and include a) processes which lead to down regulation of the genes encoding ACTH and CRH and b) more immediate effects which suppress the release of stored hormones and thereby enable the axis to adapt rapidly to changes in circulating glucocorticoid levels.
Glucocorticoids-as important regulators of the immune and inflammatory systems
Cortisol and corticosterone are the principal endogenous glucocorticoids. Both steroids are produced by most mammalian species but the ratios in which they are secreted vary from species to species. Cortisol is the predominant glucocorticoid in man. It also constitutes the active form while cortisone is its inactive precursor. In the body glucocorticoids exert widespread actions , which are essential for the maintenance of homeostasis and enable the organism to prepare for, respond to and cope with physical and emotional stress [5,6].
They promote the breakdown of carbohydrate and protein and exert complex effects on lipid deposition and breakdown. They are also important regulators of immune and inflammatory processes and are required for numerous processes associated with host defence. These properties accounts for the stress-protective actions of the steroids as they quench the pathophysiological responses to tissue injury and inflammation and, thereby, prevent them proceeding to a point where they threaten the survival of the host.
At the beginning , glucocorticoids were thought to have mainly immunosuppressive effects and with almost 67 years ago, it was shown for the first time that a synthesized version of cortisone was capable of reversing the inflammation of rheumatoid arthritis (143).In pharmachological doses glucocorticoids exert different effects than they do under physiological conditions [5,7].
At pharmacological doses (higher concentrations than physiological) are immunosuppressive at virtually every level of immune and inflammatory responses, whereas physiological levels of glucocorticoids are immunomodulatory rather than solely immunosuppressive.
It has been found that their role in immunosuppression is mainly exerted through the suppression of nuclear factor (NF)κB, which is a major factor involved in the regulation of cytokines and other immune responses [8].
The expression of cytokines like IL-1, IL-6,IFN-γ and TNF-α, is down-regulated. The net effect of glucocorticoids is a shift of cytokine production from a primarily pro-inflammatory to an anti-inflammatory pattern, roughly corresponding to Th1 and Th2, respectively. This is considered to be due mainly to down-regulation of Th1 cytokines, thus allowing dominant expression of the Th2 cytokines [3,4].
Glucocorticoids receptors (GRs)
The transcriptional actions of glucocorticoids are mediated by supposed diffusion of the
steroid hormone across the cell membrane and its binding to intracellular glucocorticoid receptors (GRs) [(9,10]. The interaction of the steroid with its receptor forms a receptor ligand complex and triggers the translocation of the receptor to the nucleus.
Two human isoforms of the GR have been identified, termed GR-α and GR-β, which originate from the same gene by alternative splicing of the GR primary transcript [(11]. GR-α is the predominant isoform of the receptor and the one that shows steroid binding activity. In contrast, GR-β does not either bind glucocorticoids or transactivate target genes. The possible physiological role of GR-β is currently a matter for debate.
In cotransfection studies, it has been shown that, when GR-β is more abundant than GR-α, GR-β acts as a dominant negative inhibitor of GR-α activity. Other investigators found no evidence for a specific dominant negative effect of GR-β on GR-α activity. Instead, it has been argued that the ability of GR-β to regulate GR-α activity in vivo would depend on its expression level relative to that of GR-α.
Increased expression of GR-β has been associated with glucocorticoid resistance [12].
A reasonable index of the activity of the HPA axis, is provided by measurements of cortisol in the circulation, although they poorly reflect the delivery of the steroids to receptors in their target cells.
In circulation most of the cortisol is bound to a carrier protein and, ín principle, only the free steroid has ready access to target cells.In healthy adults, Cortisol shows a robust diurnal pattern with the strongest secretory activity of the adrenal cortex during the early morning hours.
Shortly after awakening peak cortisol levels are observed with steadily decreasing values thereafter, except for sizable, short-term increases in response to stimuli like lunch meal, exercise or threat-provoking stressors. The peack of cortisol secretion is reached around 2 or 3 AM with only minimal levels of the steroid detectable [(13].
Annexin-1(ANXA1)as an endogenous down regulator of innate immunity
Annexin-1 (ANXA1),formely refered to as lipocortin is a mediator of the anti-inflamatory actions of glucocortids, which is expressed in peripheral blood leukocytes, particularly in cells of the innate immune system such as neutrophils and monocytes. ANXA null mice have experiments have emphasized the role of ANXA1 as an endogenous down regulator of innate immunity [14],this is localized mainly within the cytosol, but upon cell activation, it becomes rapidly mobilised to the cell surface where it acts in an autocrine/paracrine fashion by direct binding to a member of the formyl peptide receptor family, called FPRL-1[15].
As far as the mechanisms by which ANXA1 exerts its complex anti-inflammatory effects are, however, these involve the suppression of various proinflammatory genes, e.g. IL-1 and IL-6, and the blockage of eicosanoid . It has been shown that that in macrophages, to stimulate the release of IL-10 [16]. The best characterized effects of ANAX1are the pharmacological effects on neutrophils , including inhibition of migration, L-selectin shedding, suppression of enzyme release, and proapoptotic effects [17].
ANXA1 production by the peripherial blood mononuclear in human in vivo, has been shown to be induced by exogenous glucocorticoids [18].According to a recent study
ANXA1 expression in neutrophils was strongly correlated with the serum cortisol production,proposing a role for ANXA1 in mediating the anti-inflammatory effects of endogenous glucocorticoids (19]. It has been put forward the ideea based on these results, that ANXA1 expression in neutrophils might serve as an index of tissue sensitivity to endogenous glucocorticoids.
The relationship between defects in HPA axis and the incidence of autoimmune/inflammatory disease.
Following chronic inflammation or chronic activation of the HPA axis results in reciprocally protective adaptations, as in case of Cushing´s syndrome, suggesting the
development of tolerance to glucocorticoids.
The result of disturbances at any level of the HPA axis or glucocorticoid action may lead to an imbalance of the system and enhanced susceptibility to infection and inflammatory/autoimmune diseases. When comparing experimental data on inbred rat strains Fischer and Lewis rats [20] have demonstrated the association between a blunted HPA axis and susceptibility to autoimmune/inflammatory disease .
According to these studies, Lewis rats exhibit a blunted HPA axis response,compared to Fischer rats with an excessive HPA response compared to outbred rats.They are highly susceptible to a wide variety of autoimmune/inflammatory diseases, while Fischer rats are resistant to these diseases.
The autoimmune disease in Lewis rats treated with low-dose dexamethasone or transplanted intracerebroventricularly with fetal hypothalamic tissue from Fischer rats, was markedly attenuated(20].
In humans with rheumatoid arthritis has been shown a blunted HPA axis
Response,despite the fact that the basal morning cortisol levels did not differ, patients with rheumatoid arthritis showed a lower cortisol response after insulin-induced hypoglycaemia compared to healthy subjects[21]. Other studies on patients with rheumatoid arthritis concluded that there was a failure to increase cortisol secretion following surgery, despite high levels of IL-1β and IL-6, compared to subjects with chronic osteomyelitis [22].
Further studies on 24-h diurnal secretion of IL-6 and HPA axis hormones in early untreated rheumatoid arthritis, showed a positive temporal correlation between plasma levels of IL-6 and ACTH/cortisol[23].According to these results the authors
concluded that the overall activity of HPA axis remained normal and was clearly insufficient to inhibit ongoing inflammation in these patients.
In patients with SJogren`s syndrome has been also demonstrated a hypoactive HPA axis as they exhibit a blunted ACTH and cortisol response to CRH stimulation [24]. The basal morning levels of cortisol levels in patients with atopic dermatitis and systemic
lupus erythematosus, are not different compared to controls.
However, Cortisol and ACTH responses to acute psychological stress or insulin-induced
hypoglycaemia are significantly lower in these patients compared to healthy subjects [25,26].
Conclusion:
Hipotalamo-hypophyseal-adrenal (HPA) axis is the main regulator of the glucocorticoid effect on the immune system
The molecular mechanisms by which the glucocorticoids exert their negative feedback effects are complex and include a) processes which lead to down regulation of the genes encoding ACTH and CRH and b) more immediate effects which suppress the release of stored hormones and thereby enable the axis to adapt rapidly to changes in circulating glucocorticoid levels
The magnitude of the HPA response to incoming stimuli is tempered by the glucocorticoids which act at the levels of the pituitary gland and hypothalamus to suppress the synthesis and release of ACTH and CRH.
REFERENCES
1. Rugstad HE. Antiinflammatory and immunoregulatory effects of glucocorticoids: mode of action. Scand J Rheumatol Suppl. 1988; 76:257-264.
2. Buckingham JC, Loxley HD, Taylor AD, Flower RJ. Cytokines, glucocorticoids and
neuroendocrine function. Pharmacol Res. 1994; 30:35-42.
3. Schöbitz B, Reul JM, Holsboer F. The role of the hypothalamic-pituitary-adrenocortical system during inflammatory conditions. Crit Rev Neurobiol. 1994; 8:263-291.
4. Almawi WY, Beyhum HN, Rahme AA, Rieder MJ. Regulation of cytokine and cytokine receptor expression by glucocorticoids. J Leukoc Biol. 1996; 60:563-572.
5. Mulla A, Buckingham JC. Regulation of the hypothalamo-pituitary-adrenal axis by
cytokines. Baillieres Best Pract Res Clin Endocrinol Metab. 1999; 13:503-521.
6. Munck A, Náray-Fejes-Tóth A.The ups and downs of glucocorticoid physiology.
Permissive and suppressive effects revisited. Mol Cell Endocrinol. 1992; 90:C1-4.
7. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress
responses? Integrating permissive, suppressive, stimulatory, and preparative actions.
Endocr Rev. 2000; 21:55-89
8. Buckingham JC. Glucocorticoids: exemplars of multi-tasking. Br J Pharmacol. 2006;
147 Suppl 1:S258-268
9. Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D, Ferstl R, von
Eynatten M, Wendt T, Rudofsky G, Joswig M, Morcos M, Schwaninger M, McEwen B,
Kirschbaum C, Nawroth PP. A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci. 2003; 100:1920-1925.
10. Bamberger CM, Bamberger AM, de Castro M, Chrousos GP.Glucocorticoid receptor
beta, a potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest. 1995;95:2435-441.
11. Leung DY, Hamid Q, Vottero A, Szefler SJ, Surs W, Minshall E, Chrousos GP, Klemm DJ. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. J Exp Med. 1997; 186:1567-1574.
12. Oakley RH, Jewell CM, Yudt MR, Bofetiado DM, Cidlowski JA. The dominant negative activity of the human glucocorticoid receptor beta isoform. Specificity and mechanisms of action. J Biol Chem. 1999; 274:27857-27866.
13. Stone AA, Schwartz JE, Smyth J, Kirschbaum C, Cohen S, Hellhammer D, Grossman S.Individual differences in the diurnal cycle of salivary free cortisol: a replication of flattened cycles for some individuals. Psychoneuroendocrinology. 2001; 26:295-306.
14. Perretti M, Flower RJ. Modulation of IL-1-induced neutrophil migration by
dexamethasone and lipocortin 1. J Immunol. 1993; 150:992-999.
15. Hayhoe RP, Kamal AM, Solito E, Flower RJ, Cooper D, Perretti M. Annexin 1 and its bioactive peptide inhibit neutrophil-endothelium interactions under flow: indication of distinct receptor involvement. Blood. 2006; 107:2123-2130
16. Ferlazzo V, D’Agostino P, Milano S, Caruso R, Feo S, Cillari E, Parente L. Antiinflammatory effects of annexin-1: stimulation of IL-10 release and inhibition of nitric oxide synthesis. Int Immunopharmacol. 2003; 3:1363-1369.
17. Solito E, de Coupade C, Canaider S, Goulding NJ, Perretti M. Transfection of annexin 1in monocytic cells produces a high degree of spontaneous and stimulated apoptosis associated with caspase-3 activation. Br J Pharmacol. 2001; 133:217-228.
18. Strausbaugh HJ, Rosen SD. A potential role for annexin 1 as a physiologic mediator of glucocorticoid-induced L-selectin shedding from myeloid cells. J Immunol. 2001; 166:6294-6300.
19. Mulla A, Leroux C, Solito E, Buckingham JC. Correlation between the anti-inflammatory protein annexin 1 (lipocortin 1) and serum cortisol in subjects with normal and dysregulated adrenal function. J Clin Endocrinol Metab. 2005; 90:557-562.
20. Karalis K, Crofford L, Wilder RL, Chrousos GP. Glucocorticoid and/or glucocorticoid antagonist effects in inflammatory disease-susceptible Lewis rats and inflammatory diseaseresistant Fischer rats. Endocrinology. 1995; 136:3107-3112
21. Gutiérrez MA, García ME, Rodriguez JA, Mardonez G, Jacobelli S, Rivero S.
Hypothalamic-pituitary-adrenal axis function in patients with active rheumatoid arthritis: a controlled study using insulin hypoglycemia stress test and prolactin stimulation. J
Rheumatol. 1999; 26:277-281
22. Chikanza IC, Petrou P, Kingsley G, Chrousos G, Panayi GS. Defective hypothalamic
response to immune and inflammatory stimuli in patients with rheumatoid arthritis. Arthritis Rheum. 1992; 35:1281-1288.
23. Crofford LJ, Kalogeras KT, Mastorakos G, Magiakou MA, Wells J, Kanik KS, Gold
PW, Chrousos GP, Wilder RL. Circadian relationships between interleukin (IL)-6 and
hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained
hypercortisolism in patients with early untreated rheumatoid arthritis. J Clin Endocrinol
Metab. 1997;82:1279-1283
24. Johnson EO, Vlachoyiannopoulos PG, Skopouli FN, Tzioufas AG, Moutsopoulos HM.Hypofunction of the stress axis in Sjögren’s syndrome. J Rheumatol. 1998; 25:1508-1514.
25. Gutiérrez MA, Garcia ME, Rodriguez JA, Rivero S, Jacobelli S. Hypothalamicpituitary-adrenal axis function and prolactin secretion in systemic lupus erythematosus.Lupus. 1998; 7:404-408.
26. Buske-Kirschbaum A, Geiben A, Höllig H, Morschhäuser E, Hellhammer D. Altered
responsiveness of the hypothalamus-pituitary-adrenal axis and the sympathetic
adrenomedullary system to stress in patients with atopic dermatitis. J Clin Endocrinol Metab2002; 87:4245-4251.