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Original Studies |
Division of Medicine, Bristol Royal Infirmary (S.D.H., M.N., C.S., C.M.D.), University of Bristol, Bristol, BS2 8HW; and Gloucestershire Health Authority (C.F.), Victoria Warehouse, The Docks, Gloucester, GL1 2EL, United Kingdom
Address correspondence and requests for reprints to: Colin Dayan, M.D., University of Bristol, Division of Medicine, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom.
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Abstract |
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Dexamethasone inhibition of lymphocyte proliferation was measured on 54 occasions in 18 volunteers (mean age, 46 yr; range, 23–60 yr) over an 8-month period. Inter- and intra-assay variation in LSS was low when expressed as maximum inhibition achieved, Imax (2.9% and 3.4%, respectively), allowing us to demonstrate a very wide variation in Imax between healthy individuals (-6.7% to 99.7%). In contrast, within-individual variation of Imax was significantly less than between-individual variation (F test, P < 0.0001), consistent with stability of this parameter over time. No correlation was seen between LSS and glucocorticoid receptor density or affinity, suggesting a postreceptor mechanism. Serum cortisol at the time of sampling and skin sensitivity to glucocorticoids also failed to correlate with LSS.
This study suggests Imax is a sufficiently stable parameter to categorize healthy individuals according to LSS. The wide range of LSS demonstrated is striking and suggests that up to 30% of the healthy population would fail to respond to steroid therapy for severe inflammatory conditions.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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However, studies in bronchial asthma have clearly demonstrated the existence of a subset of patients who, although responsive to ß2 agonist therapy, fail to respond to steroid therapy (5). Steroid responsiveness in such patients was subsequently demonstrated to correlate poorly with initial lung function (i.e. disease severity), but much better with an in vitro measurement of lymphocyte steroid sensitivity (LSS), suppression by dexamethasone of PHA-induced proliferation of peripheral blood lymphocytes (6, 7, 8). Similar observations have since been made in rheumatoid arthritis (9), systemic lupus erythematous (3), and steroid therapy for renal transplant rejection (10). We, ourselves, have studied severe UC, a condition in which the failure rate of response to steroid therapy approaches 30%, and, once again, LSS measured in vitro was found to predict outcome more effectively than markers of disease severity (11). The concept is, therefore, emerging that the intrinsic sensitivity of an individual’s lymphocytes to glucocorticoid-mediated suppression is a major factor in determining their response to steroid therapy for inflammatory conditions. Furthermore, responsiveness can be apparently predicted by in vitro measurement of LSS.
Previous studies of LSS in healthy individuals have been limited. Corrigan et al. (6) reported "some variation" of LSS in the control population used in a study of asthma, but did not quantify this range. In other studies, only the mean, with no indication of the range of LSS seen in the control population, is given (7, 8). Walker et al. (12) reported seasonal variation in skin steroid sensitivity and serum cortisol level, however, each individual was only studied on one occasion, and the molecular parameters determining steroid sensitivity were not examined.
In view of the emerging role of LSS in predicting the outcome of steroid therapy, we wished to establish more clearly the range of steroid sensitivity in the normal population and the factors that determine it. We have, therefore, studied a cohort of healthy individuals on three occasions over an 8-month period, along with measures of glucocorticoid receptor (GR) density (number per cell) and affinity, serum cortisol level and the cutaneous vasoconstrictor response to topical steroid as a measure of steroid sensitivity in a different tissue, the skin. Our aim was to determine the stability of LSS parameters in a given individual over time along with their relationship to GR parameters and measures of steroids sensitivity in other tissues.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Eighteen healthy volunteers, 12 males and 6 females, were recruited from staff members at the University of Bristol (mean age, 46 yr; range, 23–60 yr). All subjects were assessed three times at four monthly intervals. In vitro LSS was measured on each occasion along with lymphocyte GR density and affinity, serum cortisol level, and the cutaneous vasoconstrictor response. Written, informed consent was obtained from each subject, and The Local Research Ethics Committee gave permission for this study.
On each study occasion, 50 mL blood was obtained by venepuncture between 0800 h and 1000 h to minimize any possible variability due to circadian rhythms, and transported immediately to the laboratory. Specimens were processed in a blinded manner with the operator unaware of the identity of the subject. Immediately after venesection, topical steroids were applied to measure the cutaneous vasoconstrictor response. The subject returned 24 h later to have the cutaneous vasoconstrictor response assessed (see below).
Peripheral blood mononuclear cell (PBMC) separation
Heparinized blood was mixed with an equal volume of RPMI-1640 (Life Technologies, Inc., Ltd, Paisley, UK). Aliquots (25 mL) were layered onto 15-mL aliquots of Ficoll-Hypaque (Pharmacia, Uppsala, Sweden) in 50-mL sterile conical tubes (Falcon; Becton Dickinson and Co., Cowley, UK). After centrifuging at 540 x gav for 20 min at 20 C, PBMC were recovered from the plasma/Ficoll interface using gentle suction, transferred to sterile 50-mL conical tubes, and washed twice with RPMI-1640. Cell viability was assessed by trypan blue exclusion and was always greater than 95%.
Measurement of in vitro LSS
The sensitivity of peripheral blood T-lymphocytes to glucocorticoids was assessed in a functional assay, as described previously (6). PBMC were incubated at a concentration of 4 x 105 cells/well in RPMI-1640 containing 10% FCS (Life Technologies, Inc.) in 96-well round-bottomed microtitre plates (Nunc, Life Technologies, Inc. Ltd.). The T-lymphocyte mitogen PHA (Sigma-Aldrich Corp. Ltd, Poole, UK) was added to the cultured cells at a final concentration of 5 µg/mL. Finally, dexamethasone (Sigma) was added at concentrations of 10-11 to 10-6 mol/L. Cultures were then incubated at 37 C in a humidified atmosphere with 5% CO2 for 48 h. Cell proliferation was measured by uptake of tritiated thymidine. Sterile [methyl-3H] thymidine (Amersham Pharmacia Biotech, Buckinghamshire, UK) (0.0185 MBq per well in a volume of 10 µL) was added to cell culture wells for the last 6 h of incubation. After incubation, cells were harvested onto glass fiber filter papers (Wallac, Inc., Oy, Turku, Finland) using a cell harvester (Tomtec, Orange, CT), and the incorporated radiolabel was counted using a Micro ß emission scintillation counter (Wallac, Inc.). Results were calculated as mean counts per min of triplicate cultures. Thymidine incorporation for each concentration of dexamethasone was compared with PHA-stimulated T-lymphocytes in the absence of dexamethasone.
Inter-assay variation was measured using a nonadherent steroid-sensitive human lymphoblastic cell line (CEM C7; kindly supplied by Prof. E. Brad Thompson, University of Texas). This cell line was maintained in RPMI-1640 with 10% FCS and incubated at 37 C in a humidified atmosphere with 5% CO2. Culture medium was replenished twice a week. To measure steroid sensitivity, CEM C7 cells were incubated at a concentration of 2 x 104 cells/well in RPMI-1640 containing 10% FCS in 96-well bottomed microtitre plates. Dexamethasone (Sigma) was added at concentrations of 10-11 to 10-6 mol/L. Cultures were then incubated for 48 h under the same conditions as the subjects’ lymphocytes and cell proliferation measured by thymidine incorporation described previously. LSS was measured 36 times over a period of 9 months using the CEM C7 cell line to assess interassay variation. Intra-assay variation was assessed using a single subject tested seven times on a single occasion.
Measurement of PBMC glucocorticoid receptor density and affinity
A [3H]dexamethasone radioligand binding assay was used to determine nuclear PBMC GR binding parameters, as described previously (6). PBMC obtained by buoyant density centrifugation as above were suspended in RPMI-1640 at a concentration of 4 x 106 cells/mL and incubated for 1 h at 37 C in a shaking water bath (Grant Instruments Ltd, Cambridge, UK) to remove endogenous bound glucocorticoid. Cells were centrifuged and resuspended in RPMI-1640 at 2 x 108 cells/mL and then distributed into 1.5-mL microcentrifuge tubes (Sarstedt, Leicester, UK) to obtain 4 x 106 cells per tube and incubated in RPMI-1640 buffer solution with 10 different concentrations of [3H]dexamethasone (specific radioactivity 82 Ci/mmol; Amersham Pharmacia Biotech) ranging from 1.6 to 800 nmol/L in duplicate, in the presence and absence of 103-fold excess of unlabelled dexamethasone (Sigma). The cells were incubated with labeled dexamethasone at 37 C for 1 h in a shaking water bath.
After incubation, all tubes were centrifuged at 12,000 x gav for 2 min, and 20 µL of supernatant was removed for measurement of free [3H]dexamethasone. The tubes were then cooled to 4 C in an ice bath. The cell pellet was resuspended in 1.2 mL hypotonic lysis buffer (1.5 mmol/L magnesium chloride and 10 mmol/L sodium molybdate) at 4 C. After a 30-min incubation at 4 C to complete lysis, the tubes were centrifuged at 12,000 x gav for 5 min and the supernatant was carefully aspirated. The tube was then inverted and drained for 15 min. The microcentrifuge tube tip was then cut and placed in 5 mL liquid scintillant (Optiphase; Wallac, Inc.) for counting of radioactivity. Data were analyzed by the method of Scatchard (13). GR density and affinity were measured on six occasions using the CEM C7 cell line to assess interassay variation.
Cutaneous vasoconstrictor response to glucocorticoids
The vasoconstrictor response to topical glucocorticoids was measured, as described previously (14), with minor modifications. Beclomethasone was used because of its high topical potency (15). Beclomethasone dipropionate (Sigma) was dissolved in 95% ethanol to concentrations of 1, 3, 10, 30, 100, 300, and 1000 µg/mL. Solutions were stored at 4 C and used within 2 weeks of preparation. The subject’s arm was prepared for application by trimming any hair (but not shaving the skin), and a perspex stencil with 2-cm holes was applied to the forearm. Beclomethasone solution was applied to the skin, 20 µL to each site in addition to a negative control of 95% ethanol only. After evaporation of the diluent, the sites were occluded with plastic film (Microwave Clingfilm; Tesco Stores Ltd., Cheshunt, UK) to enhance percutaneous absorption of glucocorticoid.
Solutions were applied from 0800 to 1000 h. The site was occluded for 24 h, and a tubular bandage (Tubigrip; Seton Healthcare Group plc, Manchester, UK) applied to the forearm to attenuate any affect of change in ambient temperature. The next morning, the adhesive tape and plastic film were removed and the degree of blanching was assessed 1 h later. This step allowed any tape-related erythema to resolve. Assessment was always made under standard fluorescent lighting conditions in the same room with no natural light. The ambient temperature in this observation room was maintained at 20 C. A single trained observer (CS) assessed the vasoconstriction response of all subjects and was blinded to the other measures of steroid sensitivity. Blanching was graded according to a 5 point scale: 0 = normal skin, 1 = faint blanching, 2 = obvious blanching, 3 = intense blanching, and 4 = intense blanching extending beyond the area to which solution had been applied (14). A total score for each application was produced. A high score indicates a high degree of steroid sensitivity on this test.
Serum cortisol
Cortisol was measured in the Chemical Pathology Department at Bristol Royal Infirmary using a standard chemiluminescent assay (ACS180 analyzer; Chiron Corp., Essex, UK). Serum samples for cortisol assay were obtained at the same time as blood sampling for PBMC assays. Assay variation was measured 20 times at three different cortisol concentrations of 90, 500, and 750 mmol/L. Coefficients of variation (CV) of these concentrations was 3.0%, 4.1%, and 3.9%, respectively. For comparison of variance, the CV of cortisol was taken to be 4.1%.
Statistical methods and data analysis
Parameters of steroid sensitivity from lymphocyte inhibition
assays were determined as follows. Imax was
defined as the maximal percentage inhibition of thymidine incorporation
achieved at the highest concentration of dexamethasone
(10-6 mol/L) (efficacy).
IC50 was defined as the concentration of steroid
at which thymidine incorporation is reduced to 50% of the
Imax value (potency). This was determined from
sigmoid dose-response curves fitted to the data obtained from the
inhibition assay. To illustrate derivation of these parameters,
examples of results obtained for inhibition of proliferation with
lymphocytes obtained from a steroid-sensitive subject and a
steroid-resistant subject are shown in Fig. 1
. Note that our definition of
IC50 differs from that used in previous studies
(3, 6, 8, 9, 10). In these studies, IC50 was
expressed as the concentration of dexamethasone that inhibits
proliferation of PHA-stimulated lymphocytes to 50% of the level seen
in the absence of steroid. However, in pharmacological terms,
IC50 defined in this way is a composite variable
determined both by potency (the range of steroid concentrations over
which steroid inhibition occurs) and efficacy (the maximum inhibition
achievable at high concentration: Imax).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Intra- and interassay variation for Imax
were shown to be low (Table 1 and Fig. 2A). Imax was
measured on 54 occasions in 18 healthy volunteers over an 8-month
period. Considerable between-individual variation was found, with
Imax ranging from insignificant (-6.7%) to
virtually complete (99.7%) (Fig. 2A). By comparison with this wide
range, repeated measurement of Imax revealed
relatively little variation within a given individual (Fig. 3A). Using comparisons of
variance, within-individual variation in
Imax was found to account for only 28.7% of
total variation, whereas between-individual variation contributed
70.1%. Application of the F test confirmed that between-individual
variation was significantly greater than within-individual variation
(P < 0.0001; Table 2).
This result is consistent with wide variation in
Imax between individuals, but relative stability
within each individual over time.
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Intra- and interassay variation of IC50 were
low (Table 1
and Fig. 2B). The potency of inhibition of lymphocyte
proliferation by steroids (log IC50) ranged from
-6.48 to -9.21 (Fig. 2B, between-individual variation). However, 79%
of results fell between -7.03 and -8.07 (non-log scale, 8.51–93.3
nmol/L). As a result of the similarity between individuals for most
IC50 values, analysis of variance indicated that
for IC50, within-individual variation was as
great as between-individual variation. This degree of overlap (Fig. 3B)
meant that between- and within-individual variation could not be
separated (Table 1).
Imax and GR density
Using the CEM C7 cell line to assess interassay variation, mean GR
density = 14327 (SD ± 1094) receptors/cell. CV was
acceptable (7.6%). These results are in good agreement with previous
estimates made with this cell line (16). To investigate the possibility
that variation in the maximal effect of steroids
(Imax) between individuals is determined by
variation in GR density, this parameter was measured at all time
points. Although GR density did vary between individuals (289–9560
receptors/cell), no correlation was seen between
Imax and GR density (r = 0.20,
P = 0.17), and unlike Imax,
within-individual variation was substantially greater than
between-individual variation (Table 2, F test P =
0.76).
GR affinity and IC50
GR affinity (Kd) ranged from 2.4 to 80.1
nmol/L (mean ± SD, 26.0 ± 19.3) and, hence,
fell into the same range as results for IC50
[±SD values, Kd = 6.7 - 45.3
nmol/L; IC50 (non-log scale), 8.5–93.3 nmol/L],
suggesting, as expected, that similar concentrations of steroid were
required to achieve half-maximal inhibition of proliferation and
half-maximal occupancy of GR. For a given individual, we were unable to
detect any correlation between IC50 and
Kd (r = -0.081, P = 0.58).
However, any correlation may have been obscured by experimental error
as the interassay variation in GR affinity was relatively wide (Table 1). Furthermore, the range of GR affinity in this study is higher than
previous studies, and this may also be explained by the wide interassay
variation in GR affinity measurement.
Serum cortisol levels
Morning serum cortisol levels varied between individuals in the
range of 136–819 nmol/L, as expected, from laboratory normal ranges,
with low assay variation (Table 1). Application of the F test
demonstrated that between-individual and within-individual variation
could be separately distinguished (P = 0.0008). This is
compatible with temporal stability of serum cortisol levels, as
previously demonstrated (17). However, no correlation was seen between
cortisol levels and LSS (Imax, r = -0.071;
IC50, r = 0.056), suggesting that neither
parameter is likely to be determined simply by circulating steroid
levels.
Cutaneous vasoconstrictor response
Broad variation in skin sensitivity was seen between individuals (mean score ±SD, 15.0 ± 4.6). Comparison of variance indicated that between-individual and within-individual variation could be separately distinguished (F test, P = 0.0016). Although this is compatible with within-individual stability of skin steroid sensitivity over time, no assessment of intra- and interassay variation could be made in this study, and so the contribution of assay variation to within-individual variation, is uncertain. Importantly, no correlation was seen between LSS parameters and skin steroid sensitivity (Imax, r = 0.14; IC50, r = 0.077), suggesting tissue differences in steroid sensitivity.
Association between LSS and GR parameters, cortisol level, age, and sex
Multiple linear regression using LSS (Imax and IC50) as target variable and GR density and affinity, cortisol levels, and age as candidate predictor values revealed no connection between any of the parameters. In addition, gender seemed to have no effect on LSS.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Importantly, in a given individual, Imax varied much less than might be expected over the 8-month period of study. This is the first time that temporal variation in LSS has been studied in a significant number of patients, although a previous study measuring variation over a period of weeks in three subjects also reported little variation (18). In contrast, for IC50, between-individual variation could not be distinguished from within-individual variation. Thus, Imax, but not IC50, is a suitable parameter to categorize individuals into steroid-sensitive and steroid-resistant groups. This finding is consistent with our previous observation that outcome from steroid therapy in UC correlates with Imax, but not IC50 (11). Because circulating levels of steroid during therapy for inflammatory conditions (up to 2000 nmol/L of cortisol, approximately equivalent to 100 nmol/L of dexamethasone) are typically in excess of the IC50 and closer to the concentration required to achieve Imax, it is perhaps not surprising that Imax predicts outcome more effectively. Note, however, that Imax cannot be described as an absolutely fixed characteristic because our data show that in 3 of the 18 individuals a substantial change in Imax occurred over the study period.
In this study, we have analyzed our results differently to previous
studies. Previous studies have not quoted a value for
Imax, and calculated IC50
as the concentration of dexamethasone required to reduce proliferation
to 50% of PHA-stimulated values, rather than the concentration
required to achieve 50% of Imax (true potency).
Because for most individuals Imax is considerably
less than 100%, calculation of IC50 by these two
methods frequently produces very different values (Fig. 1). Using the
previous method, calculation of IC50 in
steroid-resistant individuals results in values of "more than
10-6 mol/L". However, calculated by our
method, values for IC50 are broadly of similar
value to GR Kd, as would be expected if steroid
bound to GR mediates the effect on lymphocyte proliferation. In
addition, we believe that our finding of stability in
Imax, but not IC50, further
validates our approach to calculating these parameters.
The factors responsible for the wide range of steroid sensitivity remain uncertain. Rare cases of individuals with steroid resistance due to GR receptor defects have been described (19). Such individuals are clinically mildly Addisonian despite high circulating cortisol levels (up to five times normal levels) (20, 21). Such a mechanism clearly does not underlie the range of steroid sensitivity seen in this study because morning cortisol levels were not raised, neither GR density nor affinity correlated with either measure of LSS (Imax or IC50), and GR parameters were not grossly abnormal.
Steroids exert their effects on cells via binding to cytoplasmic GR, which then translocate to the nucleus and bind either to DNA, typically resulting in gene transactivation (22), or to transcription factors such as activator protein-1 (23) typically producing transrepression (24). Our data are consistent with a postreceptor basis for the variation of LSS because no correlation was seen between GR parameters and Imax. This is, perhaps, to be expected because over the range of GR affinity measured in this study (Kd 2.4–80.1 nmol/L) even cells with the lowest affinity would have more than 95% GR occupied at the dexamethasone concentration used to measure Imax (1000 nmol/L) (25). Abnormalities of GR-activator-1 binding have been demonstrated in steroid-resistant asthma (26), also consistent with a postreceptor mechanism mediated by transcription factors.
In this study there was no correlation between LSS and the cutaneous vasoconstrictor response to glucocorticoids. This relationship has not been directly examined before. However, cutaneous steroid sensitivity of patients with steroid-resistant asthma (who would be expected to have steroid-resistant lymphocytes) has been examined previously, and a correlation between asthma steroid responsiveness and skin steroid sensitivity has been reported (14). The basis of this discrepancy with our findings is uncertain. Although we made efforts to reduce observer error, the skin test is more subjective than lymphocyte testing. Furthermore, seasonal variation in skin steroid sensitivity has been described and may result in discrepancies vs. LSS (12). Our data are consistent with differences in tissue susceptibility to steroids. In addition, our failure to find a correlation between Imax and serum cortisol (reflecting hypothalamic sensitivity to steroids) also suggests tissue variation in steroid sensitivity. Additional studies using tests of steroid sensitivity in a variety of tissues are required to clarify this area.
Overall, our data suggest that LSS can be usefully estimated in vitro by measurement of Imax and that this reveals up to 30% of the healthy population as having significantly steroid-resistant lymphocytes. What are the implications for the individuals concerned? In the absence of disease, such individuals can clearly remain healthy. However, if, as we have observed, a high proportion of such individuals remain steroid resistant over time, it seems likely that they will represent the cohort most likely to fail to respond to steroid therapy, should an inflammatory condition develop. It is certainly interesting to note that the failure rate of steroid therapy is similar across a broad range of inflammatory conditions (1, 2, 3, 4) and is consistent with an intrinsic resistance to steroids of 30% in the general population. For steroid-resistant individuals, our confirmation that LSS can be measured in a clinically meaningful way makes it possible to explore ways to pharmacologically modify LSS, an approach that is likely to offer the best hope of improving the outcome of steroid therapy in these individuals.
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Acknowledgments |
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Footnotes |
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2 A Digestive Disorders Foundation Research Fellow.
Received April 1, 1999.
Revised July 30, 1999.
Accepted August 4, 1999.
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