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*
Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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secretion and IFN
regulatory factor-1 expression in both NK and T cells. This occurred
even though the level of expression of IL-12 receptors and
IL-12-induced Janus kinase phosphorylation remained unaltered. However,
dexamethasone markedly inhibited IL-12-induced phosphorylation of Stat4
without altering its expression. This was specific, as IL-4-induced
Stat6 phosphorylation was not affected, and mediated by the
glucocorticoid receptor, as it was antagonized by the glucocorticoid
receptor antagonist RU486. Moreover, transfection experiments showed
that dexamethasone reduced responsiveness to IL-12 through the
inhibition of Stat4-dependent IFN regulatory factor-1 promoter
activity. We conclude that blocking IL-12-induced Stat4
phosphorylation, without altering IL-4-induced Stat6 phosphorylation,
appears to be a new suppressive action of glucocorticoids on the Th1
cellular immune response and may help explain the
glucocorticoid-induced shift toward the Th2 humoral immune
response. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and
TNF-
(9). Similarly, glucocorticoids caused a marked
reduction of IL-12 secretion by human monocytes and, hence, a decreased
capacity to produce IFN- and an increased ability to induce IL-4
secretion by T cells (10). The differentiation of naive CD4+ T cells into Th1 and Th2 cell types is influenced by cytokines produced early in response to the Ag triggering the immune response (12, 13). Specifically, IL-12 promotes Th1 cell differentiation, which leads to cell-mediated immunity, while IL-4 promotes Th2 cell differentiation, which drives allergic and humoral-mediated immunity. The Th1 and Th2 immune responses in large measure depend upon the activation of transcription factors Stat4 and Stat6, respectively (14). Stat4 knockout mice have a deficient cellular immune response, while Stat6 knockout mice have an impaired humoral immune response (15, 16, 17, 18).
Understanding the regulatory effects of glucocorticoids on cytokine signaling would help to further clarify how these hormones influence Th1 cellular and Th2 humoral immune responses. Recently, it was reported that glucocorticoids suppressed the Th1 immune response by inhibiting the responsiveness of activated PBMC to IL-12, through down-regulation of the IL-12R ß1- and ß2-chain expression (19). Here, we report that glucocorticoids decrease IL-12 responsiveness through another mechanism, namely inhibition of Stat4 phosphorylation. This novel mechanism contributes to the immunosuppressive action of glucocorticoids on the Th1 cellular immune response and the associated shift toward the Th2 humoral immune response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The following reagents were purchased: recombinant human IL-12 and IL-4 (R&D Systems, Minneapolis, MN), anti-phosphotyrosine Ab (4G10) (Upstate Biotechnology, Lake Placid, NY), polyclonal rabbit anti-Stat4 and anti-Stat6 Ab (Santa Cruz Biotechnology, Santa Cruz, CA), and polyclonal rabbit anti-Jak2, anti-Jak1, and anti-Tyk2 Ab (Upstate Biotechnology). Polyclonal rabbit anti-Jak3 and anti-Stat5a Abs were produced as previously described by this laboratory (20). Human IL-2 was provided by Dr. C. Reynolds (National Cancer Institute, Frederick, MD). NK3.3 were provided by Dr. J. Kornbluth (Arkansas Cancer Research Center, Little Rock, AR). NIH3T3 were provided by the American Type Culture Collection (Manassas, VA). PBMC from healthy donors were isolated by Ficoll-Paque gradient centrifugation, activated with PHA (2 µg/ml) for 72 h and cultured for an additional day in the presence of IL-2 (40 IU/ml), as described previously (21, 22). Cell viability, as determined by trypan blue exclusion, thymidine incorporation, and FACS (annexin V/PI) analysis (Trevigen, Gaithersburg, MD), was not affected by dexamethasone treatment.
IFN- ELISA
NK3.3 cells and T lymphocytes (5 x
106/ml) were rested in 1% FCS medium for 4
h, pretreated with 10-7 M of dexamethasone for
various times, and then stimulated with IL-12 (20 ng/ml) for 10 h.
The cell cultures were centrifuged, and the supernatant was removed and
stored at -20 °C. IFN- was measured using a specific immunoassay
(R&D Systems) according to the manufacturer’s instructions.
RNase protection assay
NK3.3 cells and T lymphocytes were rested for 4 h, pretreated with dexamethasone at 10-7 M for various times, and then stimulated with IL-12 (20 ng/ml) for 4 h. RNA extraction was performed (RNAgents; Promega, Madison, WI), and mRNA expression was evaluated by RNase protection. RNase protection assay was performed as follows: 32P-labeled RNA probes were synthesized using SP6 RNA polymerase or T7 RNA polymerase for the IFN regulatory factor (IRF)-1 probe and the multiprobe template set (Riboquant; PharMingen, San Diego, CA). DNA was digested with DNase I (Boehringer Mannheim, Indianapolis, IN), and RNA probes were extracted with phenol/chloroform and precipitated with ethanol. Labeled RNA probes were hybridized overnight with target RNA (5 µg) at 56°C and were digested with T1 RNase (Life Technologies, Gaithersburg, MD). The protected mRNA fragment was extracted with phenol and chloroform, precipitated with ethanol, resolved on a 6% denaturing polyacrylamide gel, and subjected to autoradiography. Gene transcripts were identified by the length of the protected fragments. Equal loading of RNA was estimated from the amounts of protected fragments of two housekeeping genes, L32 and GAPDH.
Immunoprecipitation and immunoblotting
NK3.3 cells and T lymphocytes were pretreated with different concentrations of dexamethasone for various times, resuspended in 1 ml of serum-free medium (2 x 106 NK3.3 cells, 50 x 106 T cells), and stimulated with either IL-12 (20 ng/ml) or IL-4 (20 ng/ml). Following stimulation, cells were washed once in PBS and lysed on ice in a buffer containing 0.5% Triton X-100, 50 mM Tris-HCl, pH 7.5, 300 mM NaCl, 2 mM EDTA, 200 µM Na3VO4, 10 µg/ml aprotinin, 10 µg/ml leupeptin, and 2.5 µM p-nitrophenyl p-guanidinobenzoate on ice for 30 min. Immunoprecipitation with anti-Stat or Jak Abs and subsequent SDS-PAGE were performed as described previously (20, 21, 22) with detection by enhanced chemiluminescence (LumiGLO, Kirkegaard & Perry Laboratories, Gaithersburg, MD).
Transfection experiments
NIH3T3 cells were seeded in six-well plates (1.8 x 105 per well). Eighteen hours later, the cells were transfected, using lipofectamine (Life Technologies), according to the manufacturer’s protocol. The cells were transfected 8 h with the following plasmids: p3xGAS-luciferase (kindly provided by Dr. Richard Pine, Public Health Research Institute, New York, NY) (0.2 µg), CMV-ß-galactosidase (0.2 µg), and, as indicated, with pEF-BOS-IL-12R ß1 (0.2 µg), pEF-BOS-IL-12R ß2 (kindly provided by Dr. Uli Gubler, Roche Nutley, NJ) (0.6 µg), pCDNA3-Stat 4 (kindly provided by Dr. J Ihle, St. Jude Children’s Hospital, Memphis, TN) (0.2 µg), and pCDNA3-Tyk2 (0.2 µg). The transfected cells were pretreated with 10-7 M dexamethasone (6 h), washed once, and then stimulated with IL-12 (10 ng/ml), where indicated, for another 6 h. Cells were lysed, and luciferase and ß-galactosidase activities were determined using the Dual-Light Kit according to manufacturer’s instruction (Tropix, Bedford, MA). The results were normalized for each sample by dividing luciferase activity by ß-galactosidase activity. The results are representative of three independent experiments performed in triplicate.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IRF-1 expression
IL-12-dependent production of IFN- is an important step in the
generation of a cell-mediated immune response. As shown in Fig. 1
A, IL-12 induced IFN-
secretion in NK3.3 cells (lanes 1 and 2),
and dexamethasone pretreatment (10-7 M) was
found to block this induction (lanes 3 and
4). The inhibition of IL-12-induced IFN- secretion was
observed after 6 h of dexamethasone pretreatment and was maximal
after 18 h. To better characterize the kinetics of inhibition, we
analyzed the levels of IFN- mRNA expression. As is evident in Fig. 1B, stimulation of NK3.3 with IL-12 for 4 h resulted in
increased IFN- expression (lanes 1 and
2). Notably, 6 h and 18 h of dexamethasone
pretreatment nearly completely blocked the IL-12-induced IFN-
expression in NK3.3 cells (lanes 3 and 4).
This result was also confirmed in T lymphocytes (data not shown).
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gene, we next analyzed the expression of another gene important
for Th1 differentiation, IRF-1 (Fig. 1
C). We and others have
recently reported that IL-12 up-regulates IRF-1 expression
(lanes 1 and 2) (23, 24).
Interestingly, 6 and 18 h of pretreatment with dexamethasone
substantially reduced IRF-1 expression (lanes 3 and
4). Equal amounts of GAPDH and L32 transcripts confirmed
that equal amounts of RNA were used (Fig. 1, B and
C). Dexamethasone does not alter the level of expression of IL-12 receptors
To understand the possible mechanism of the decreased
responsiveness to IL-12 by dexamethasone, we first examined whether
dexamethasone influenced IL-12R (ß1- and
ß2-chains) expression in NK 3.3 cells.
Dexamethasone was previously shown to decrease IL-12 receptor
expression in peripheral blood mononuclear cells stimulated with
immobilized anti-CD3 for 3 days (19). We evaluated the
IL-12R (ß1- and
ß2-chains) expression after shorter incubations
with dexamethasone (Fig. 2A).
Treatment with dexamethasone from 1 to 18 h did not alter the
levels of these cytokine receptors (lanes 1–6). We
also analyzed IL-4R (- and the common -chains) expression; it
remained unchanged by dexamethasone treatment (Fig. 2B,
lanes 1–6). These results underscore the specific decrease
in expression of IFN- and IRF-1. Equal amounts of GAPDH and L32
transcripts confirmed that equal amounts of target RNA was used.
Similar results were also obtained in T lymphocytes (data not
shown).
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The absence of modulation of the cytokine receptor mRNA expression
suggested that dexamethasone may be acting at another site, presumably
downstream of IL-12 receptor engagement. The earliest defined step of
IL-12 signaling is the phosphorylation of Jak2 and Tyk2. Thus, we next
looked at the effect of dexamethasone treatment on the phosphorylation
of these tyrosine kinases. As previously shown in Fig. 3A, IL-12 induced
phosphorylation of Jak2 and Tyk2 within 20 min (lane
2) (22). However, preincubation of the cells with
dexamethasone (10-7 M) for 6 or 18 h had no
effect on the phosphorylation of Jak2 and Tyk2 (Fig. 3A,
lanes 3 and 4). The levels of Jak2 and Tyk2
protein were also unchanged, as determined by reblotting with Abs to
Jak2 and Tyk2. Thus, neither the phosphorylation nor the protein
expression of Jak2 and Tyk2 were modulated by dexamethasone treatment.
We also analyzed the effect of dexamethasone treatment on IL-4
signaling, namely activation of Jak1 and Jak3. As shown in Fig. 3B, IL-4 induced phosphorylation of these kinases within 20
min (lane 2). Preincubation of the cells with
dexamethasone (10-7 M) for 6 or 18 h had no
effect on the phosphorylation of these kinases (Fig. 3B,
lanes 3 and 4). The levels of Jak1 and Jak3
protein were also unchanged, as determined by reblotting with the
relevant Abs.
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Once Jaks are activated, they phosphorylate cytokine receptors
allowing the recruitment and phosphorylation of Stat proteins, which in
turn dimerize, translocate to the nucleus, and activate gene
transcription (14). IL-12-dependent regulation of the
IFN- and IRF-1 genes is thought to be mediated by Stat4. Therefore,
we next examined whether dexamethasone could affect IL-12-induced Stat4
phosphorylation. As previously shown, stimulation of NK3.3 cells with
IL-12 (20 ng/ml) resulted in Stat4 phosphorylation (Fig. 4; A, lanes 2 and
5; B and C, lane 2;
C, lanes 2 and 5) (21).
Interestingly, pretreatment with dexamethasone
(10-7 M) inhibited IL-12-induced Stat4
phosphorylation (Fig. 4A, lanes 3, 4,
6, and 7). This was confirmed when a more
detailed time course of inhibition was analyzed (Fig. 4B,
lanes 3–6); inhibition was observed as early as
2 h. Moreover, this inhibition was evident at doses of
dexamethasone varying from 10-10 to
10-7 M (Fig. 4C, lanes
3–6). This effect was mediated by the glucocorticoid
receptor, as 10-7 M RU486, a specific
glucocorticoid receptor antagonist, abrogated the inhibition of Stat4
phosphorylation (Fig. 4D, lane 3 vs
6). However, Stat4 protein levels were not altered by
dexamethasone treatment; reblotting with anti-Stat4 Ab showed that
its expression was unchanged (Fig. 4, A–D, lower
panels).
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induce Stat4
phosphorylation (25). To assess whether the inhibition of
Stat4 phosphorylation was specific to IL-12, we examined the effect of
dexamethasone pretreatment on IFN--induced Stat4 phosphorylation and
observed that this was also inhibited by dexamethasone pretreatment
(data not shown). This was consistent with our findings that early
events in IL-12 signaling (i.e., Jak activation and receptor
expression) were not affected by dexamethasone.
To ascertain that dexamethasone inhibition of Stat4 phosphorylation was
of general importance, we sought to determine whether it also occurred
in normal human T lymphocytes. As shown in Fig. 4E, IL-12
induced Stat4 phosphorylation in activated T lymphocytes within 20 min
(lane 2). Consistent with the results in the NK cell
line, dexamethasone pretreatment was also found to block the
IL-12-induced Stat4 phosphorylation in T cells (lanes
3 and 4).
Th2 immune responses are poorly inhibited or even enhanced by
glucocorticoids (5, 6, 7, 8, 9, 10, 11). In fact, glucocorticoids increase
the synthesis of Ig E by IL-4-stimulated human lymphocytes
(5, 6, 7). It would then be expected that IL-4-dependent
phosphorylation of Stat6 should be resistant to dexamethasone.
Therefore, we next tested the specificity of the inhibition of
IL-12-induced Stat4 phosphorylation in T lymphocytes, examining the
effect of dexamethasone on IL-4-induced Stat6 phosphorylation. As
expected, IL-4 induced Stat6 phosphorylation (Fig. 4E,
lane 6). In contrast to Stat4, dexamethasone pretreatment
did not affect IL-4-induced Stat6 phosphorylation (Fig. 4E,
lane 7 and 8).
Dexamethasone pretreatment decreases IL-12-induced IRF-1 promoter activity
To further characterize the specific inhibition of Stat4 activation by dexamethasone, we next examined its effect in a heterologous system using transfected NIH3T3 cells. In this model, we and others have previously shown that the IRF-1 induction by IL-12 is dependent upon Stat4 (23, 24). This system allowed us to dissect the elements involved in the IL-12 signaling pathway and to study the effect of dexamethasone.
First, IL-12 enhanced IRF-1 promoter activity (Fig. 5, lane 7); this induction was
Stat4 dependent because mock-transfect cells did not show any
luciferase activity after IL-12 stimulation in the absence of Stat4
(Fig. 5, lane 3). Dexamethasone pretreatment alone had no
effect on IRF-1 promoter activity in mock- and Stat4-transfected cells
(Fig. 5, lanes 2 and 6). However, IL-12-induced
IRF-1 promoter activity was decreased after dexamethasone pretreatment
(Fig. 5, lane 8).
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, lane 9). Similarly, dexamethasone pretreatment led
to a decreased IRF-1 promoter activity (Fig. 5, lane 10).
This suggested that the inhibition of Stat4 activation by dexamethasone
occurred through a IL-12R-independent mechanism. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and enhances
the cytolytic functions of activated NK and CD8+
T cells (26). IL-12 exerts its effect by inducing tyrosine
phosphorylation of Jak2 and Tyk2, which in turn phosphorylate the
transcription factor Stat4 (21, 22), responsible for the
regulation of a number of key IL-12-inducible genes (23, 24, 26). In this study, we report that dexamethasone pretreatment
inhibits Stat4 phosphorylation without altering other early steps of
IL-12 signaling, namely the expression of IL-12R
ß1- and ß2-chains and
IL-12-induced Tyk2 and Jak2 phosphorylation. Simultaneously,
IL-4-induced Stat6 phosphorylation remained unchanged. Thus, this study
suggests that glucocorticoids, by preventing Stat4 phosphorylation,
decrease IL-12 responsiveness, diminishing the induction of genes such
as those of IFN- and IRF-1. Several studies have shown the opposing effect of glucocorticoids on the cellular and humoral immune responses (4, 5, 6, 7). One clear mechanism is their action on cytokine secretion; glucocorticoids inhibit the secretion of Th1 and enhance the production of Th2 cytokines (8, 9, 10, 11). Stat4 knockout mice have an impaired Th1 immune response with decreased Th1 cytokine and enhanced Th2 cytokine sectretion (16). IRF-1 knockout mice also have a deficient Th1 immune response (27). Indeed, we and others have shown that IL-12 induces IRF-1 expression through Stat4 activation (23, 24). Previous reports have suggested that glucocorticoids suppress the Th1 immune response by inhibiting IL-12 secretion by monocytes/macrophages and dendritic cells (9, 10, 11). Here, we show that glucocorticoids decrease the ability of T cells to respond to IL-12. Thus, glucocorticoids appear to block Th1 lymphocyte development by both inhibiting IL-12 secretion and Stat4-mediated IL-12 signaling. In addition, the differential action of glucocorticoids on IL-12 and IL-4 signaling might explain the observed shift of the immune response toward the Th2 humoral immune response.
A previous study reported a decreased IL-12 responsiveness by
dexamethasone via down-regulation of IL-12R ß1-
and ß2-chain expression (19).
However, the authors analyzed only the long-term effect of
dexamethasone on activated lymphocytes and the down-regulation of IL-12
receptors could only be shown after a 3-day culture of
anti-CD3/TCR-stimulated T cells in the presence of dexamethasone.
In contrast, in our study, decreased IL-12-induced Stat4
phosphorylation was observed as early as 2 h after dexamethasone
pretreatment, at a time when IL-12 receptor expression was unaffected.
Although these two phenomena are distinct, they might coexist and
together contribute to decreased IL-12 responsiveness in T lymphocytes.
Indeed, because the down-regulation of STAT4 activation results in
decreased IFN- secretion (Fig. 1) and IFN- has been demonstrated
to increase expression of IL-12R ß2
(28), the two observations may be directly linked.
Glucocorticoids could inhibit Stat4 phosphorylation through a number of potential mechanisms, several of which have already been identified. These include the modulation of expression or activity of different factors that play a role in the attenuation of cytokine signaling, such as phosphatases, suppressors of cytokine signaling proteins (SOCS and cytokine inhibitor Src homology 2-containing protein (CIS)), or protein inhibitors of activated Stats (PIAS). Finally, glucocorticoids might inhibit the expression of some factor that is required for the activation of Stat4. A potential negative regulation of a positive acting factor may also be envisaged, although such a factor as not been described yet.
Src homology 2 domain-containing tyrosine phosphatases like Src homology protein (SHP)-1 and SHP-2 can attenuate cytokine and hormone signaling (29, 30, 31, 32, 33, 34). Glucocorticoids might inhibit cytokine signaling by inducing or activating these or other tyrosine phosphatases (29). Presently, we cannot determine whether SHP-1 or SHP-2 associate with IL-12R ß2, the subunit containing several tyrosine residues, and whether glucocorticoids affect this association, as no reagents that immunoprecipitate IL-12R ß2 are currently available. However, this mechanism of action seems unlikely, granted that the inhibition of Stat4 phosphorylation by dexamethasone appears not to be IL-12R dependent. Furthermore, the lack of inhibition of IL-4-induced Stat6 phosphorylation in T cells suggests that this phosphatase may be specific for Stat4. While it is well recognized that Stat phosphorylation is specific, specific Stat phosphatases have yet to be identified.
Another alternative explanation would be the regulation of different
members of the family of SOCS (also known as JAK-binding protein or
STAT-induced STAT inhibitor) (35, 36, 37). For instance, IL-10
suppresses IFN-- and IFN--dependent Stat1 phosphorylation, and
this is accompanied by the up-regulation of SOCS-3 (38).
However, the inhibition of IL-12-induced Stat4 phosphorylation without
altering Jak activation argues against an involvement of SOCS; SOCS-1
is thought to bind to Jaks, inhibiting their activity
(35, 36, 37). Nevertheless, the first identified inhibitor of
Stat signaling, CIS, was reported not to bind to Jaks but rather to
interact with phosphotyrosine residues in the erythropoeitin receptor
and IL-3 ßc, thereby preventing Stat phosphorylation (37, 39). Thus, CIS might be a good candidate for a steroid inducible
inhibitor of Stat4 phosphorylation.
Finally, the recently described PIAS1 and -3 interact with and block Stat1 and -3 DNA-binding activities but do not alter Stat phosphorylation (40, 41). No Stat4-specific PIAS family member has been characterized as yet; moreover, PIAS wihout altering Stat phosphorylation may not play a role in this condition. Further studies will be needed to clarify the underlying mechanism responsible for the inhibitory action of glucocorticoids on Stat4 phosphorylation.
Activation of the HPA axis by proinflammatory cytokines results in the release of endogenous glucocorticoids, which in turn suppress innate and specific immune responses (3). The inflammatory response of streptococcus cell wall-induced arthritis in susceptible Lewis and resistant Fischer rats is inversely related to the magnitude of their HPA axis response to inflammatory mediators. Moreover, the glucocorticoid receptor antagonist RU486 renders Fischer rats susceptible to arthritis (42, 43). Also, adrenalectomy in Lewis rats with experimental allergic encephalomyelitis, a Th1 cell-mediated autoimmune disease, leads to a chronically active disease, while substitutive replacement of glucocorticoids induces recovery from the disease (44, 45). Thus, endogenous glucocorticoids might decrease susceptibility to Th1-type immune diseases by lowering T cell responsiveness to IL-12.
Glucocorticoids have been used for 50 years as potent immunosuppressants in the therapy of Th1 inflammatory and autoimmune diseases. Glucocorticoids render treated patients immunocompromised, with an increased susceptibility to intracellular infections. The ability of glucocorticoids to specifically suppress Th1 cellular immunity is well described but poorly understood. Our study suggests that glucocorticoid-mediated inhibition of Stat4 phosphorylation may represent a major underlying mechanism of the specific suppression of cellular immunity by glucocorticoids.
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Footnotes |
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2 D.F. and J.G. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. J. J. O’Shea, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, Bethesda, MD 20892. E-mail address:
4 Abbreviations used in this paper: HPA, hypothalamic-pituitary-adrenal; IRF-1, IFN regulatory factor-1; Jak, Janus kinase; Tyk, tyrosine kinase; SOCS, suppressor of cytokine signaling; CIS, cytokine inhibitor Src homology 2-containing protein; PIAS, protein inhibitor of activated Stat; SHP, Src homology protein.
Received for publication August 30, 1999. Accepted for publication December 3, 1999.
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 A. Steensberg, A. D. Toft, H. Bruunsgaard, M. Sandmand, J. Halkjar-Kristensen, and B. K. Pedersen Strenuous exercise decreases the percentage of type 1 T cells in the circulation J Appl Physiol, October 1, 2001; 91(4): 1708 - 1712. [Abstract] [Full Text] [PDF]
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J. W. Mills, L. Ryan, R. LaCourse, and R. J. North Extensive Mycobacterium bovis BCG Infection of Liver Parenchymal Cells in Immunocompromised Mice Infect. Immun., May 1, 2001; 69(5): 3175 - 3180. [Abstract] [Full Text] [PDF]
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M.-N. Avice, M. Rubio, M. Sergerie, G. Delespesse, and M. Sarfati CD47 Ligation Selectively Inhibits the Development of Human Naive T Cells into Th1 Effectors J. Immunol., October 15, 2000; 165(8): 4624 - 4631. [Abstract] [Full Text] [PDF]
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 M. Bianchi, C. Meng, and L. B. Ivashkiv Inhibition of IL-2-induced Jak-STAT signaling by glucocorticoids PNAS, August 15, 2000; 97(17): 9573 - 9578. [Abstract] [Full Text] [PDF]
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