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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 1 557-562
Copyright © 2005 by The Endocrine Society

BRIEF REPORT

Correlation between the Antiinflammatory Protein Annexin 1 (Lipocortin 1) and Serum Cortisol in Subjects with Normal and Dysregulated Adrenal Function

Abeda Mulla, Carel LeRoux, Egle Solito and Julia C. Buckingham

Department of Cellular and Molecular Neuroscience (A.M., E.S., J.C.B.), Division of Neuroscience and Psychological Medicine, and Department of Metabolic Medicine (C.L.), Division of Investigative Sciences, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom

Address all correspondence to: Professor Julia Buckingham, Department of Cellular and Molecular Neuroscience, Division of Neuroscience and Psychological Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom. E-mail: j.buckingham{at}imperial.ac.uk; or e.solito{at}imperial.ac.uk. Address requests for reprints to Dr. Egle Solito. E-mail: esolito{at}imperial.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Annexin 1 (ANXA1), a Ca2+ and phospholipid binding protein, is an important mediator of the antiinflammatory actions of glucocorticoids. However, although inflammatory responses in man are sensitive to alterations in adrenocortical function, the relationship between endogenous cortisol and ANXA1 expression has not been explored. Accordingly, we measured serum cortisol levels and ANXA1 expression in peripheral blood leukocytes from subjects with normal and dysregulated cortisol secretion before and 30 min after a standard corticotrophin (ACTH) test. Our data demonstrate a highly significant correlation between the serum cortisol concentration and the expression of ANXA1 in neutrophils, both before and after ACTH treatment, and thus suggest that ANXA1 may serve as a marker of glucocorticoid sensitivity. They also reveal a correlation between ANXA1 and the serum gonadotrophins, LH and FSH, and an age-related reduction in ANXA1 expression in lymphocytes.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GLUCOCORTICOIDS (GCS) HAVE been used clinically for more than half a century as immunosuppressive and antiinflammatory drugs. Initially, their powerful therapeutic effects were considered by physicians and physiologists to be pharmacological and distinct from the physiological functions fulfilled by the endogenous GC, cortisol. However, in recent years it has become apparent that endogenous GCs have an important role in regulating the host-defense system and that dysregulation of the secretion and/or activity of cortisol may compromise immune/ inflammatory cell function, thereby disrupting homeostatic physiology (1).

GCs exert their biological actions principally by increasing or decreasing the expression of specific target genes and, hence, the proteins they encode. Annexin 1 (ANXA1, also known as lipocortin 1) is one such GC-inducible protein and shows powerful antiinflammatory actions in a number of animal models (2). It is expressed in rodent and human peripheral blood leukocytes (PBLs), particularly monocytes and neutrophils, and is also found in abundance in inflamed tissues. Its importance as a mediator of the antiinflammatory actions of GCs is amply supported by evidence that animals, in which ANXA1 activity has been ablated by gene deletion (3) or immunoneutralization (4), show exacerbated inflammatory responses that are resistant to suppression by exogenous GCs. Reports of autoantibodies against ANXA1 in a number of patients with chronic inflammatory disease (e.g. rheumatoid arthritis) have raised the possibility that ANXA1 deficiency may contribute to the pathogenesis of inflammatory disease and/or GC resistance (5, 6). However, whereas there is strong evidence that exogenous GCs regulate ANXA1 production in man (7, 8) the possibility has not been explored that endogenous GCs fulfill a similar role and that alterations in ANXA1 expression may contribute to the alterations in host-defense function associated with disorders of cortisol secretion. To address this question, we examined the correlation between the serum cortisol concentration and the expression of ANXA1 in PBLs in subjects with normal and disordered cortisol secretion.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The study was performed on 17 patients (seven males, 10 females, aged 27–70 yr, see Table 1Go for details at presentation) who were attending the Endocrine Clinic at Charing Cross Hospital (London, UK) for investigation of hypothalamo-pituitary-adrenocortical (HPA) function and were therefore undergoing a routine ACTH test. Ethical permission for the study was granted by Riverside Research Ethics Committee (RREC 2271), and informed consent was obtained from each of the subjects before the study.


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  		TABLE 1. Age, sex, medical and drug history of each patient prior to testing together with the serum cortisol concentrations (µg/dl) before and 30 min after the administration of ACTH1–24 (conversion factor for SI units = 27.59)

 
After an overnight fast and collection of a basal blood sample (between 0830 and 1115 h), each subject was injected im with 250 µg synthetic ACTH1–24 (tetracosactin, Synacthen, Novartis, Frimley, Surrey, UK). A second blood sample was taken 30 min after the injection. The blood samples were processed for analysis of serum hormones and ANXA1 expression in PBLs. Serum cortisol (chemiluminescence assay) and other hormones (LH, FSH, GH, prolactin, TSH, T3, T4, insulin, IGF-I by ELISA) were determined in the Endocrinology Laboratory, Charing Cross Hospital, according to routine protocols. ANXA1 was determined by flow cytometry (9). Briefly, PBLs were harvested after red cell lysis (Immuno-Lyse solution, Coulter Corp., Miami, FL), permeabilized with saponin (0.0025%, Sigma Chemical Co., Poole, UK) and washed in PBS (Sigma). They were then incubated in PBS at 22 C first for 1 h with either a specific anti-ANXA1 polyclonal antiserum [raised in rabbit against full-length human recombinant ANXA1, diluted 1:100] (10) or anti-sea urchin {alpha}-tubulin monoclonal antibody (control, 1:100, Sigma) and, subsequently, for 15 min in fluorescein isothiocyanate-tagged secondary antisera (sheep antirabbit, diluted 1:600, or goat antimouse, diluted 1:250, respectively, Chemicon International, Temecula, CA). In all cases, antibody-free and secondary-antibody-alone controls were run in parallel. After centrifugation, the cells were resuspended in buffer for flow cytometric analysis (FACSCalibur, Becton & Dickinson, Oxford, UK). Flow cytometry permits the separation of cells according to size (forward scatter) and granularity (side scatter). It thus allows the separation of PBLs into subpopulations of neutrophils, monocytes, and lymphocytes (Fig. 1AGo); cell debris and dead cells are eliminated by presetting the threshold according to the manufacturer’s instructions. Preliminary studies confirmed the effectiveness of the separation process by immunostaining for cell-specific antigens, CD14 for monocytes and CD16 for neutrophils. A total of 10,000 events/sample was counted. In all cases the neutrophils comprised 50–70% of the total cell population; no shifts in the cell population were observed in individuals within the study, presumably because the 30-min time frame was too short for steroid-induced cell margination to occur. Comparability between samples was controlled by rigorous calibration using a microsphere calibration kit (Becton & Dickinson). Correlations between ANXA1 expression and serum hormones were determined by calculation of the Pearson coefficient.



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  		FIG. 1. Positive correlations between the serum cortisol concentration and the expression of ANXA1 in neutrophils before and after administration of ACTH1–24. A, Scattergram showing the separation of lymphocytes (L), neutrophils (N), and monocytes (M) according to forward (cell size) and side scatter (cell granularity). B, Typical flow cytometry profile showing ANXA1 expression in neutrophils. C and D, Correlations between the serum cortisol concentration and ANXA1 expression in neutrophils before (C) and 30 min after (D) injection of ACTH1–24 (250 µg, im). Before ACTH, r = 0.534, P < 0.05; ACTH stimulated, r = 0.647, P < 0.01. For measurement of fluorescein isothiocyanate fluorescence by flow cytometry, a total of 10,000 events were counted. The mean fluorescence intensity of the cell population was measured and corrected for background fluorescence by subtraction of fluorescence detected in cells incubated in secondary antibody alone. Parallel measures of {alpha}-tubulin confirmed that the cells were effectively permeabilized with saponin.

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The majority of patients studied showed basal serum cortisol concentrations in the normal range and responded to ACTH with a robust rise in cortisol (increment > 7 µg/dl), attaining serum levels of more than 18 µg/dl. However, three patients showed evidence of adrenal insufficiency with low serum cortisol levels before (<6.5 µg/dl) and after (<11 µg/dl) ACTH stimulation (patients 4, 5, and 13), whereas two more patients showed elevated basal serum cortisol levels (>30 µg/dl) and further marked responses to ACTH (patients 6 and 9, Table 1Go). Patients 4, 5, and 13 had confirmed secondary adrenal insufficiency and were being treated with hydrocortisone; this treatment was withdrawn 24 h before testing. Patient 6 had been treated previously for Cushing’s disease.

In line with previous observations (7, 9), ANXA1 was readily detected in PBLs (Fig. 1BGo) and was localized mainly to neutrophils and monocytes with only small amounts of the protein evident in lymphocytes. There was a significant correlation between ANXA1 expression in the total PBL population and the serum cortisol concentration before (r = 0.622, P < 0.01) and after (r = 0.570, P < 0.05) ACTH administration. Thus, ANXA1 was almost undetectable before and after ACTH treatment in the three patients who showed a low basal serum cortisol (<6.5 µg/dl) and modest response to ACTH (<11 µg/dl). On the other hand, the two patients with raised basal serum showed increased ANXA1 expression vs. those with normal adrenal function. When the data were reanalyzed on the basis of individual leukocyte populations, this correlation was evident only for neutrophils (basal, r = 0.534, P < 0.05; ACTH stimulated, r = 0.647, P < 0.01; see Fig. 1Go, C and D). Basal ANXA1 expression was also positively correlated with both LH (r = 0.667, P < 0.01) and FSH (r = 0.696, P < 0.01) but not with any of the other hormones measured (Table 2Go). In addition, although there was no correlation between serum cortisol and age (r = 0.063, P > 0.05), ANXA1 expression in lymphocytes, but not in monocytes or neutrophils, showed a significant negative correlation with age (r = –0.652, < 0.05, Fig. 2Go).


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  		TABLE 2. Correlation between annexin 1 (ANXA1) expression in peripheral blood leukocytes and the serum concentrations of various hormones in human subjects

 


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  		FIG. 2. Negative correlation between ANXA1 expression (determined by fluorescence-activated cell sorter analysis and expressed as mean fluorescence intensity) in lymphocytes and the age of the patient (r = –0.652, P < 0.05).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
To the best of our knowledge, this is the first study to explore the relationship between the serum cortisol concentration and ANXA1 protein expression in PBLs from subjects with normal and dysregulated HPA function. Our data demonstrate that ANXA1 levels in neutrophils, but not in monocytes or lymphocytes, correlate positively with the serum cortisol both before and after a standard ACTH1–24 test. They thus suggest that measures of neutrophil ANXA1 may provide a sensitive index of tissue sensitivity to endogenous cortisol. Moreover, because ANXA1 is an antiinflammatory protein (2, 3), these data also raise the possibility that changes in ANXA1 expression may contribute to the altered inflammatory responses evident in patients with dysregulated cortisol secretion.

Our measures of ANXA1 were made by fluorescence-activated cell sorting analysis. This robust method allows quantification of ANXA1 protein in subpopulations of isolated cells and is used routinely for this purpose in our own (10) and other (4, 7, 9) laboratories. In line with published studies (4, 7, 9), we found substantial amounts of the protein in neutrophils and monocytes but only modest amounts in lymphocytes.

Substantial evidence supports the view that glucocorticoids play an important part in regulating ANXA1 gene and protein expression. In support of this premise, adrenalectomy decreases ANXA1 mRNA expression in the rat (11), whereas dexamethasone and hydrocortisone induce de novo ANXA1 synthesis (12). Similarly, administration of GCs causes a marked increase in PBL ANXA1 expression in normal human subjects (7). However, not all tissue/cell types are equally responsive to GCs (13), and other factors, e.g. the local cytokine environment, appear to modulate the ANXA1 response to steroids (14). The data reported here suggest that endogenous GCs exert a particularly important influence on ANXA1 expression in neutrophils and that these cells are sensitive both to subtle changes in the resting cortisol concentration and to the rises in cortisol secretion induced by injection of ACTH1–24. Measures of neutrophil ANXA1 may thus provide a sensitive index of the tissue sensitivity to endogenous cortisol. In contrast, Goulding et al. (7) found that the regulatory effects of exogenous steroids on PBL ANXA1 expression were directed predominantly at the monocytes. This difference could reflect the time course of the two studies because Goulding et al. (7) made their observations 2 h after the steroid injection, whereas in the present study, measurements were made 30 min after the administration of ACTH1–24. Indeed, given the time lag of the cortisol response to ACTH1–24, the robust ANXA1 response in neutrophils reported here is perhaps surprising. Because leukocytes express ACTH receptors (15), it is possible that it is the injected ACTH1–24 and not the newly synthesized cortisol that is up-regulating ANXA1 in our study. However, this seems unlikely because ANXA1 expression is not augmented by the elevations in circulating ACTH produced in vivo by adrenalectomy (11, 12, 16) or ex vivo by stimulation of pituitary tissue with CRH or forskolin (12, 17). A more likely explanation of the prompt rise in ANXA1 reported here is that the newly synthesized cortisol is acting via a nongenomic action. In support of this premise, we recently described rapid (within 30 min) positive effects of glucocorticoids on ANXA1 expression in other tissues that are blocked by inhibitors of translation but not transcription and may therefore require translation of preformed mRNA (10, 17).

Several lines of evidence support the view that ANXA1 is an important mediator of the powerful antiinflammatory actions of GCs (2). In particular, ANXA1-null mice show substantially exaggerated inflammatory responses and resistance to the suppressive effects of glucocorticoids (3, 18). Similarly, neutralizing anti-ANXA1 antiserum reverse the antiinflammatory effects of glucocorticoids in several animal models of inflammation (4). In the light of evidence that cortisol deficiency is associated with an increased incidence of allergic and autoimmune inflammatory disease (e.g. asthma, glomerulonephritis, and giant cell arteritis) (19, 20) and that hypercortisolemia results in immunosuppression and an associated increased susceptibility to infection (1), our finding that ANXA1 expression in neutrophils is strongly correlated with the serum cortisol concentration suggests a role for ANXA1 in mediating the antiinflammatory effects of endogenous GCs. The data thus concur with reports (21) that the sensitivity of monocyte ANXA1 to regulation by exogenous GCs is impaired in subjects with rheumatoid arthritis, a condition that has also been associated with impaired HPA function (21, 22), and with evidence of autoantibodies to ANXA1 in cohorts of patients with rheumatoid arthritis and other inflammatory disease (23).

The mechanisms by which ANXA1 exerts its antiinflammatory effects are complex. The protein may be generated by and released from several cell types, including neutrophils and monocytes/macrophages, and exert diverse effects that include suppression of various proinflammatory genes, e.g. cytoplasmic phospholipase A2, inducible nitric oxide synthase, and IL-1 and -6 (3, 18, 24), blockade of eicosanoid production (25) and inhibition of neutrophil migration (26). The function of ANXA1 in lymphocytes is ill defined, although reports that the protein is more prevalent in T cells and natural killer cells than B-lymphocytes (27), suggesting that it may play a role in the processes regulating cell-mediated immunity. The age-related decline in ANXA1 in lymphocytes may therefore be related to the reduction in immune function.

Our finding that the basal ANXA1 levels correlate with serum gonadotrophins was surprising and has not been reported before. There is, however, evidence that sex steroids, in particular estrogens, exert tissue-specific effects on the regulation of ANXA1 gene expression (28) (Solito, E., K. Froud, Q. Liu, and J. C. Buckingham, unpublished observations) and that ANXA1 contributes to the processes regulating testicular testosterone production (29). Furthermore, ANXA1 knockout mice exhibit a number of unexpected functional sexual dimorphisms (3) and disturbances in the tissue responses to gonadal hormones (30).

In conclusion, we suggest that changes in PBL ANXA1 expression may serve as an index of tissue sensitivity to endogenous glucocorticoids and that such changes might contribute to the altered susceptibility to autoimmune, inflammatory and infectious disease associated with GC dysregulation. ANXA1 has recently been identified as a marker of hairy cell leukemia (27). However, to date, only two members of the annexin family have been implicated in the pathogenesis of human disease, viz. annexins 2 and 5 in acute promyelocytic leukemia and the antiphospholipid syndrome, respectively (31). The present data raise the possibility that dysregulation of ANXA1 expression in disorders of cortisol secretion/activity may represent a third type of annexinopathy.


   Footnotes
 
This work was supported by the Wellcome Trust (Grant 069234/B/02/Z) and Medical Research Council.

First Published Online October 27, 2004

Abbreviations: ANXA1, Annexin 1; GC, glucocorticoid; HPA, hypothalamo-pituitary-adrenocortical; PBL, peripheral blood leukocyte.

Received June 28, 2004.

Accepted October 15, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Munck A, Naray-Fejes-Toth A 1994 Glucocorticoids and stress: permissive and suppressive actions. Ann NY Acad Sci 746:115–130[Abstract]
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  4. Perretti M, Ahluwalia A, Harris JG, Harris HJ, Wheller SK, Flower RJ 1996 Acute inflammatory response in the mouse: exacerbation by immunoneutralization of lipocortin 1. Br J Pharmacol 117:1145–1154[Medline]
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