INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

INTERLEUKIN-1 (IL-1) is a fundamental mediator of immune and inflammatory defense responses. However, IL-1 can also promote host-destructive processes. For example, it induces superoxide anion release by neutrophils, which can result in edematous lung injury and pancreatic -cell death (16, 22). Additionally, IL-1 stimulates collagenase and proteoglycanase secretion from synovial cells, resulting in cartilage matrix degradation (33), and therefore has been associated with the pathogenesis of inflammatory diseases such as rheumatoid arthritis and lupus nephritis (12). IL-1 activity is mediated by two agonist isoforms, IL-1, which is mainly cell associated and has juxtacrine actions, and IL-1, which is the predominant secreted protein and has paracrine and endocrine actions. IL-1 is collectively defined as the two agonist isoforms. Because of the diverse, potentially destructive functions of IL-1, multiple control pathways have evolved to prevent undesirable tissue damage.

Several regulators acting at the site of inflammation modulate the biological action of IL-1. One regulatory pathway involves increased secretion of IL-1 receptor antagonist (IL-1ra) by activated monocytes. IL-1ra competitively inhibits the binding of IL-1 agonists to both type I and type II IL-1 receptors on target cells (2). Another regulatory pathway involves secretion of a soluble form of the IL-1 type II receptor (sIL-1RII), which binds secreted IL-1 before it reaches target cells thus preventing activation (8).

Glucocorticoids are potent systemic anti-inflammatory agents that are used clinically to modulate the inflammatory response. The endogenously produced glucocorticoid, cortisol (hydrocortisone), regulates IL-1 secretion through a feedback mechanism between the hypothalamic-pituitary-adrenal (HPA) axis and the monocyte (4, 32). This is most clearly demonstrated in animal models of endotoxemia, which are associated with increased ACTH and corticosterone secretion. IL-1 is a primary mediator of HPA axis activation, because pretreating animals with anti-IL-1 receptor antibodies diminished the endotoxin-induced increase in ACTH (30). Moreover, intravenous injection of IL-1 activates the hypothalamus, increasing corticotropin-releasing factor (CRF) and ACTH secretion (29). The net result is an IL-1-induced increase in glucocorticoid secretion, which, in turn, inhibits IL-1 secretion by decreasing IL-1 mRNA expression and stability (20, 21). This negative feedback loop limits inflammation and prevents a potentially detrimental overactive immune response.

Animal studies suggest that gender-related differences exist in the immune activation of the HPA axis. For example, central injection of IL-1 in female rats resulted in higher plasma ACTH and corticosterone concentrations than in males (29). In humans, age- and gender-related differences in the sensitivity of the HPA axis to feedback inhibition by glucocorticoids have been reported. In healthy individuals, cortisol regulates its own secretion by inhibiting CRF and ACTH secretion through a feedback mechanism. Heuser et al. (17) demonstrated that dexamethasone pretreatment in women did not inhibit CRF-stimulated secretion of ACTH and cortisol to the same magnitude as in men. In older subjects, stimulation of the HPA axis resulted in a more prolonged secretion of ACTH and cortisol compared with younger subjects (17). Furthermore, cortisol infusion was less effective at inhibiting the secretion of ACTH in older subjects (40). Gender differences in the sensitivity of the HPA axis to feedback inhibition by glucocorticoids are more pronounced with increasing age. Compared with older men, cortisol concentrations in older women remained elevated for a longer period of time after HPA axis activation (15). Thus there is an age- and gender-related decline in the ability to turn off the HPA axis after activation, resulting in a stronger and more prolonged HPA response.

Paradoxically, the incidence of inflammatory diseases such as Hashimoto's thyroiditis, systemic lupus erythmatosus, and rheumatoid arthritis is much greater in women compared with men (1). Furthermore, the risk of inflammatory diseases increases as the individual ages (19). These outcomes may be reconciled if a reduced sensitivity to cortisol-mediated feedback inhibition on inflammatory cytokine secretion exists in women and in the elderly compared with young men. Although age and gender differences in the sensitivity of the HPA axis are well documented, the sensitivity of the mononuclear cell to inhibition by glucocorticoids has not been examined between genders or with aging. The purpose of this study was to test the hypothesis that secretion of the principal soluble IL-1 isoforms (IL-1 and IL-1ra) and soluble receptor (type II) by mononuclear cells of women and older individuals is less sensitive to inhibition by hydrocortisone than the cells of young men.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

Subjects. All subjects were healthy, not taking any medication, and they gave an informed consent to participate in this study. Six healthy women (28.8 ± 1.7 yr of age, not taking oral contraceptives) and six healthy men (27.5 ± 2.3 yr of age) were included in this study. Baseline data from the young men (Table 1) have been included in a previously reported study (11). The women were tested twice, once during the midfollicular phase and once during the midluteal phase of the menstrual cycle. To examine the effects of age, seven healthy postmenopausal women not receiving hormone replacement therapy (62.1 ± 1.6 yr of age) and seven healthy older men (66.2 ± 3.4 yr of age) were recruited. Subjects representing all age and gender groups were recruited and tested concurrently. All procedures were approved by the Pennsylvania State University Human Investigation Review Committee.

Blood samples. A venous blood sample was drawn from each subject between 0800 and 0900 via the antecubital vein into a heparinized syringe. An aliquot of the blood was removed and centrifuged, and the plasma was separated and frozen at 70°C until analysis of plasma sIL-1RII and cortisol concentration. The remaining blood sample was used for mononuclear cell isolation and determination of IL-1 isoform and soluble receptor secretion in cell culture.

Cell isolation and culture. Peripheral blood mononuclear cells (PBMC) were isolated by density centrifugation with Ficoll-Hypaque (Histopaque, Sigma, St. Louis, MO). The mononuclear cell layer was aspirated and washed three times with 0.9% NaCl. The cells were resuspended in phenol red-free RPMI supplemented with 100 U/ml penicillin, 100 µg/ml streptomycin, 100 mM HEPES, 0.2 mM L-glutamine (all from Sigma), and 1% heat-inactivated autologous plasma (56°C for 1 h). Sodium hydrocortisone (Solu-Cortex, Upjohn, Kalamazoo, MI) was added to the cultures in concentrations of 0, 50, 100, 500, or 1,000 ng/ml. In stimulated cultures, 1 ng/ml lipopolysaccharide (LPS) Escherichia coli (E. coli 055:B5, Sigma) was added 60 min after the hydrocortisone. Cells were incubated in 24-well polystyrene plates (Corning Glass Works, Corning, NY) at a density of 2.5 × 10⁶ cells/ml for 24 h at 37°C in a humidified 5% CO₂ chamber. After incubation, the supernatants were collected and centrifuged to remove cells, and they were frozen at 70°C until analysis of IL-1, IL-1ra, and sIL-1RII concentrations. All containers used for cell culture were disposable and endotoxin free; all solutions were injectable grade or endotoxin tested.

Cytokine measurements. The IL-1ra and sIL-1RII concentrations were measured by ELISAs developed in our laboratory. For the IL-1ra ELISA, 96-well high binding ELISA microtiter plates (Corning Glass Works) were coated with 50 µl of a 20 µg/ml protein A solution (Sigma) in 15 mM Na₂CO₃ and 34.8 mM NaHCO₃, pH 9.6 (coating buffer), and incubated overnight at 4°C (25). The plates were washed with PBS, pH 7.0, with 0.5% Tween 20 (PBST), followed by the addition of 50 µl of 4 µg/ml of monoclonal IL-1ra antibody (R&D Systems, Minneapolis, MN) in coating buffer and incubated overnight at 4°C. The plates were washed with PBST blocked with 200 µl of 1% BSA-PBS for 1 h followed by washing. Recombinant human IL-1ra standards (R&D Systems) or culture supernatants (100 µl) were added to the wells, and the plates were incubated overnight at 4°C. The plates were washed followed by sequential incubations with 100 µl of 0.2 µg/ml biotinylated polyclonal IL-1ra antibody (R&D Systems) and conjugated streptavidin-peroxidase (Pierce, Rockford, IL). After washing the plates, 100 µl of 2,2'-azinobis(3-ethylbenzthiazoline-sulfonic acid) (ABTS, Sigma Chemical, St. Louis, MO) substrate was added for 60-90 min followed by a reading on a spectrophotometer at 405 nm (Multiskan Microplate Reader, Labsystems, Needham Heights, MA). The sensitivity of the ELISA was 30 pg/ml in RPMI. Ten nanograms per milliliter of IL-1 or IL-1RII produced <10% interference in the assay.

The methodology for the sIL-1RII ELISA was similar to that for the IL-1ra except for the following. The plates were not coated with protein A before the addition of the primary antibody. The plates were coated with 2 µg/ml of monoclonal sIL-1RII antibody (R&D Systems) in 0.1 M NaCO₃, pH 8.2. The secondary antibody, biotinylated polyclonal sIL-1RII antibody (R&D Systems), was added at 0.1 µg/ml. The sensitivity was 15 pg/ml in RPMI. Ten nanograms per milliliter of IL-1 or IL-1ra produced <10% interference in the assay.

IL-1 concentrations were determined by a commercially available ELISA (Cistron Biotechnology, Pine Brook, NJ). Briefly, culture supernatants were added to antihuman monoclonal IL-1 antibody-coated plates and detected with a polyclonal rabbit anti-human antibody directed against mature IL-1. The sensitivity of this ELISA was 10 pg/ml in RPMI. Ten nanograms per milliliter of sIL-1RII or IL-1ra produced <10% interference in the assay. Samples from each age and gender group were included on each ELISA plate.

Cortisol assay. Plasma cortisol was determined by a commercially available solid phase competitive inhibition RIA (Coat-A-Count, Diagnostics Products, Los Angeles, CA). The sensitivity of the RIA was 1 µg/dl in plasma samples.

Statistical analysis. Data are expressed as means ± SE. All data without hydrocortisone in the culture were analyzed by a one-way ANOVA to determine between-group differences. All data examining hydrocortisone sensitivity were normalized by expressing as a percentage of the control condition (no hydrocortisone in the culture) and analyzed by a two-way repeated measures ANOVA (group × hydrocortisone concentration). Differences in the dose response to hydrocortisone between groups were indicated by the interaction term of the two-way ANOVA. The criterion for statistical significance was set at P < 0.05. The mean of the follicular and luteal measurement for each young woman is presented unless specifically stated otherwise. Differences between follicular vs. luteal phase were assessed by paired t-tests. Analyses were performed on a Macintosh computer using SuperANOVA software version 1.11 (Abacus Concepts, Berkeley, CA).

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

IL-1 isoform and soluble receptor secretion in the absence of hydrocortisone. In unstimulated PBMC, IL-1 secretion was undetectable in all groups, whereas both IL-1ra and sIL-1RII were detected. No significant age-related differences were observed in these cultures (Table 1). However, when sIL-1RII secretion was analyzed by gender, irrespective of age, cells from the men secreted significantly greater amounts (540 ± 104 pg/ml) compared with the women (244 ± 57 pg/ml, P = 0.011, Fig. 1A). Secretion of sIL-1RII by cells from the young women was signifcantly higher in the follicular phase compared with the luteal phase (P = 0.048, Fig. 1B).

View larger version (321539K): [in this window] [in a new window]   Fig. 1.   A: secretion of soluble interleukin-1 receptor type II (sIL-1RII) in vitro by unstimulated peripheral blood mononuclear cells (PBMC) isolated from young (solid bars) and older (hatched bars) men and women (follicular and luteal phases combined).  P = 0.011, women vs. men, irrespective of age. Data are expressed as means ± SE. B: menstrual cycle variations in secretion of sIL-1RII. Five of six women exhibited >3-fold higher secretion rates in follicular phase compared with luteal phase (* P = 0.048). C: plasma IL-1RII concentrations in young and older men and women (same bar identifications as in A); * P = 0.033 young women vs. young men.

Stimulation of PBMC with LPS significantly increased both IL-1 and IL-1ra secretion but significantly decreased sIL-1RII secretion in all groups. There were no significant age- or gender-related differences between the groups for the LPS-stimulated cultures.

Plasma sIL-1RII and cortisol. Plasma concentrations of sIL-1RII were also examined to determine if age or gender differences existed. Overall, plasma sIL-1RII concentrations were higher in the men (7.8 ± 0.5 ng/ml) than in the women (6.7 ± 0.2 ng/ml, P = 0.047). When stratified by age group, plasma sIL-1RII was significantly greater in the young men (8.32 ± 0.63 ng/ml) compared with the young women (6.48 ± 0.20 ng/ml, P = 0.033, Fig. 1C), but not the older men compared with the older women (P = 0.85). With the exception of one outlier in the older male group, a significant correlation was observed between in vitro sIL-1RII secretion by unstimulated cells and circulating plasma concentrations (r = 0.405, P = 0.03, data not shown).

Endogenous cortisol may influence the secretion of IL-1 isoforms by PBMC, therefore plasma cortisol concentrations were determined from the same blood used to isolate PBMC. No significant differences in plasma cortisol concentrations were detected between the groups. Plasma cortisol concentrations were highest in the older women (17.6 ± 2.4 µg/dl) and lowest in the older men (13.8 ± 2.4 µg/dl).

Hydrocortisone regulation of IL-1 secretion. IL-1 secretion in unstimulated cultures was not detectable by the methods employed. In LPS-stimulated cultures, hydrocortisone significantly decreased IL-1 secretion in a dose-dependent manner (P < 0.0001). As shown in Fig. 2, there were no significant age- or gender-specific differences in the sensitivity of PBMC to hydrocortisone. In fact, PBMC sensitivity to hydrocortisone for IL-1 secretion was almost identical for all the groups examined.

View larger version (27K): [in this window] [in a new window]   Fig. 2.   Secretion of IL-1 in vitro by PBMC incubated with 1 ng/ml of lipopolysaccharide (LPS) and doses of hydrocortisone ranging from 0 to 1,000 ng/ml. Hydrocortisone significantly decreased IL-1 secretion over doses tested (P = 0.0001). Groups represented: young men, n = 6 (); young women, n = 6 (); older men, n = 7 (); and older women, n = 7 (). In Figs. 2-4, data are normalized to control condition (no hydrocortisone in culture, absolute values given in Table 1) and expressed as means ± SE. Columns of numbers below data points indicate P values for each group at each hydrocortisone concentration compared with control condition without hydrocortisone.

Hydrocortisone regulation of IL-1ra secretion. In unstimulated cultures, hydrocortisone significantly decreased IL-1ra secretion in a dose-related manner (P = 0.0001). Doses of hydrocortisone in the 50-100 ng/ml range decreased IL-1ra secretion by 60-82%, and 1,000 ng/ml of hydrocortisone nearly abolished IL-1ra secretion (Fig. 3A). There were no significant age- or gender-specific differences in IL-1ra secretion. In LPS-stimulated cultures, hydrocortisone significantly decreased IL-1ra secretion over the doses examined (P = 0.0001). In contrast to unstimulated conditions, the lower doses of hydrocortisone decreased IL-1ra by only 30-45% (Fig. 3, A and B), whereas 1,000 ng/ml of hydrocortisone decreased IL-1ra secretion by ~70%. Thus hydrocortisone was approximately half as inhibitory in LPS-stimulated cultures compared with unstimulated cultures. There were no age- or gender-specific differences in the sensitivity of PBMC to hydrocortisone in LPS-stimulated cultures.

View larger version (2928K): [in this window] [in a new window]   Fig. 3.   A: secretion of sIL-1 receptor antagonist (sIL-1ra) in vitro by PBMC incubated with hydrocortisone concentrations ranging from 0 to 1,000 ng/ml. Hydrocortisone significantly decreased IL-1ra secretion over doses tested (P = 0.0001). Groups represented: young men, n = 5 (); young women, n = 6 (); older men, n = 6 (); and older women, n = 7 (). B: secretion of IL-1ra in vitro by PBMC incubated with 1 ng/ml LPS and 0-1,000 ng/ml of hydrocortisone. Hydrocortisone significantly decreased IL-1ra secretion over doses tested (P = 0.0001). Groups represented: young men, n = 6 (); follicular phase women, n = 6 (); older men, n = 7 (); and older women, n = 7 (). Columns of numbers above data points indicate P values for each group at each hydrocortisone concentration compared with control condition without hydrocortisone.

Hydrocortisone regulation of sIL-1RII secretion. Secretion of sIL-1RII in the control cultures exhibited a biphasic response to hydrocortisone that was dependent on gender (Fig. 4A). An intermediate dose of hydrocortisone (100 ng/ml) significantly decreased sIL-1RII secretion in all groups (P < 0.0005), except in the young women (P = 0.19). However, higher concentra- tions of hydrocortisone (500-1,000 ng/ml) did not cause further inhibition of sIL-1RII secretion in the cells from the men. These higher concentrations of hydrocortisone were less effective at inhibiting sIL-1RII secretion in the cells from the women. When the data were analyzed irrespective of age, cells from the women exhibited a significantly different dose response to hydrocortisone from the cells from the men (P = 0.0001).

View larger version (2830K): [in this window] [in a new window]   Fig. 4.   A: secretion of sIL-1RII in vitro by PBMC incubated with 0-1,000 ng/ml of hydrocortisone. Cells from women exhibited a significantly different dose response to hydrocortisone from cells from men (P = 0.0001), regardless of age. Groups represented: young men, n = 6 (); young women, n = 5 (); older men, n = 6 (); and older women, n = 5 (). B: secretion of sIL-1RII in vitro by PBMC incubated with 1 ng/ml LPS and hydrocortisone ranging from 0-1,000 ng/ml. Hydrocortisone significantly increased sIL-1RII secretion across range of hydrocortisone tested in all groups (P = 0.0001). Cells from young women exhibited a significantly different dose response to hydrocortisone from cells from young men (P = 0.022). Groups represented: young men, n = 5 (); young women, n = 6 (); older men, n = 7 (); and older women, n = 7 (). Columns of numbers above data points indicate P values for each group at each hydrocortisone concentration compared with control condition without hydrocortisone.

As shown in Fig. 4B, hydrocortisone increased sIL-1RII secretion in LPS-stimulated cultures in a dose-dependent manner (P = 0.0001). High concentrations of hydrocortisone (500-1,000 ng/ml) increased sIL-1RII secretion considerably. For example, sIL-1RII secretion by the cells from the young men increased from 35 ± 20 to 591 ± 191 ng/ml, and the secretion by the cells from the young women increased from 143 ± 88 to 648 ± 188 ng/ml. The cells from the young women exhibited a significantly different dose response to hydrocortisone from the cells from the young men (P = 0.022).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

The results of this study indicate that although hydrocortisone influences the secretion of all IL-1-related proteins studied, only sIL-1RII secretion was influenced in a gender-dependent manner. Mononuclear cells isolated from the men secreted more sIL-1RII under basal (non-LPS stimulated) conditions and were more responsive to high concentrations of hydrocortisone than the cells from the women. Age did not affect glucocorticoid sensitivity to any of the proteins examined under any conditions. The cells were cultured in 1% autologous plasma, therefore it is possible that humoral factors were transferred that influenced cellular responsiveness. However, gender-specific differences in cytokine secretion have been observed for cells cultured with a synthetic serum replacement (10). The finding that the circulating concentration of sIL-1RII is greater in the men is consistent with a previous report that IL-1 binding capacity was higher in the plasma from the men compared with the women, and this binding capacity correlated with plasma sIL-1RII concentration (7).

Soluble IL-1RII appears to regulate IL-1 bioavailability by binding secreted IL-1 agonists ( or ). The addition of sIL-1RII to cultured fibroblasts or synovial cells decreased the IL-1-induced secretion of PGE₂ and collagenase (6). Additionally, compared with wild-type controls, local phorbol 12-myristate 13-acetate-induced inflammation was reduced in transgenic mice (27). These studies implicate sIL-1RII as a natural inhibitor of IL-1-induced inflammation.

The mechanism(s) that determines gender differences in glucocorticoid-mediated inhibition of sIL-1RII secretion would not seem to be at the level of glucocorticoid receptor expression. Although decreased receptor numbers have been reported in the liver and thymus of female rats compared with male rats (13), no gender differences have been demonstrated in the glucocorticoid receptor number or affinity in human mononuclear cells (18, 36). Alternatively, progesterone can enhance the dissociation of glucocorticoids from their receptors (35), which may result in decreased glucocorticoid responsiveness. However, the present study included postmenopausal women whose progesterone concentrations would be low, thus reducing the possibility that progesterone is competing with pharmacological concentrations of hydrocortisone. Finally, if receptor expression were the key factor, then all three IL-1-associated proteins measured in this study would exhibit sex-related sensitivity to hydrocortisone.

Glucocorticoid receptor expression in mononuclear cells has been reported to decrease with age (3) which may compromise IL-1 regulation between the HPA axis and the monocyte. However, the present data indicate that the responsiveness of mononuclear cells from subjects in their seventh decade of life (on average) is similar to cells from subjects in their third decade.

An interesting finding of this study is that LPS differentially affected the secretion of IL-1 isoforms and sIL-1RII. Both IL-1 and IL-1ra secretion rates were significantly increased by LPS, but sIL-1RII secretion was decreased. These data are in accordance with others (26, 31) that demonstrated LPS decreased sIL-1RII mRNA expression in human mononuclear cells. Moreover, the activation state of the cell actually reversed the influence of hydrocortisone on sIL-1RII secretion in the present study. In unstimulated cells, hydrocortisone decreased sIL-1RII secretion, whereas in LPS-stimulated cells it markedly increased sIL-1RII secretion (18- to 33-fold). Brown et al. (5) have demonstrated that LPS and dexamethasone synergistically increase sIL-1RII secretion, although they did not report a dexamethasone-induced effect on sIL-1RII secretion in unstimulated cells. However, they did not detect basal levels of sIL-1RII as demonstrated in this study and by others (9, 31).

In contrast to the present data obtained with mixed mononuclear cell cultures, Colotta et al. (9) reported that dexamethasone significantly increased sIL-1RII secretion and mRNA expression in unstimulated, purified human monocytes. Conflicting data are reported regarding sIL-1RII secretion by unstimulated T cells (23, 24). However, phytohemagglutinin- or antigen-stimulated T lymphocytes do express IL-1RII mRNA and secrete the soluble receptor (23, 24). B lymphocytes also secrete sIL-1RII, however, the contribution of B lymphocytes in an isolated mononuclear cell preparation is ~5% (34). Hydrocortisone-induced decreases in sIL-1RII secretion may involve a negative influence of lymphocytes on the monocytes. The culture conditions used in the present study do correspond to in vivo conditions because unstimulated sIL-1RII secretion correlated with plasma sIL-1RII concentrations of the subjects.

Polymorphonuclear neutrophils (PMN) also express IL-1RII and secrete a soluble form, however, regulation by LPS and glucocorticoids is different from that in mononuclear cells. LPS significantly increased sIL-1RII secretion by PMN (14), and dexamethasone increased both mRNA expression and secretion of sIL-1RII in unstimulated PMN (28). In contrast to the 60-kDa form secreted by PBMC, PMN secrete a 45-kDa form of sIL-1RII with the difference being attributed to glycosylation (9, 28). The differential regulation of sIL-1RII secretion by various cell types suggests that the function of secreted sIL-1RII may be dependent on the cellular source. It is possible that under basal conditions, circulating sIL-1RII originates from PBMC. During bacterial infection, however, the contribution of mononuclear cells declines, whereas the contribution of neutrophils increases. Van der Poll et al. (37) reported that administration of a low dose endotoxin did not change plasma concentrations of sIL-1RII, which may be due to a change in the relative contribution of PMN and PBMC to the total cellular secretion of sIL-1RII.

Counterbalancing the activity of IL-1 with specific IL-1 inhibitors provides important regulatory control of both systemic and local inflammation. The endogenously secreted anti-inflammatory cytokines IL-4 and IL-13 increase both sIL-1RII and IL-1ra secretion by mononuclear cells (9, 38, 39). In contrast, the present data demonstrated that hydrocortisone increased sIL-1RII secretion but decreased IL-1ra secretion in LPS-stimulated cells. Thus the mechanisms of glucocorticoid action are different from the mechanisms controlling regulation within the cytokine network.

Perspectives

The results of this study also indicated that the activation state of the mononuclear cells determined how they responded to hydrocortisone in terms of sIL-1RII secretion. During gram-negative infection, cortisol is expected to increase sIL-1RII secretion, which, in turn, would downregulate LPS-induced IL-1 activity. However, several physiological stressors, including ultraviolet radiation and oxidative stress, induce IL-1 secretion; under these circumstances, cortisol may promote IL-1 activity by downregulating sIL-1RII.