| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Pediatrics, Stanford University, Stanford, CA 94305
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
synthesis and decrease IL-4 synthesis by CD4+ T
cells. The reduction in IL-12 production by corticosteroid-treated
macrophages decreased their ability to induce IFN- and increased
their ability to induce IL-4 synthesis in Ag-primed CD4+ T
cells. Splenic adherent cells from mice treated in vivo with
dexamethasone also displayed a reduced capacity to produce IL-12. These
results help to resolve previous conflicting observations regarding the
effects of corticosteroids on cytokine production by T cells, and
indicate that while corticosteroids may directly inhibit Th1 and Th2
cytokine production in T cells, corticosteroids, by reducing IL-12
production in APCs, have the potential to indirectly enhance Th2
cytokine synthesis. Therefore, treatment of diseases such as allergy
with chronic corticosteroids may indirectly exacerbate the course of
the disease, which is caused primarily by the overproduction of Th2
cytokines in allergen-specific CD4+ T cells. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B, which binds to the transcription factor
NF-B and inhibits its capacity to translocate to the nucleus (5, 6, 7).
However, the effect of corticosteroids on IL-4 production in
lymphocytes is controversial. Some investigators have demonstrated that
corticosteroids inhibit IL-4 production in lymphocytes (8), whereas
other investigators have demonstrated that corticosteroids enhance IL-4
synthesis in T cells both in vivo and in vitro (9, 10, 11). Determination
of the precise effect of corticosteroids on IL-4 synthesis is
important, since enhancement of IL-4 synthesis by corticosteroids may
be clinically undesirable, for example in the setting of allergic
disease and asthma, and may reduce enthusiastic use of corticosteroid
therapy in asthma, as recommended by the National Institutes of
Health (12).
Since many cell types respond to corticosteroids, conflicting results
regarding cytokine synthesis in different studies may be due to a
neglect in some studies of evaluating the effects of corticosteroids on
the APCs used to activate T cells. We therefore wished to distinguish
the effects of corticosteroids on the APC used to activate the T cell
from direct effects of corticosteroids on the T cell, and performed
experiments in which only the APC, and not the T cell, was exposed to
corticosteroids. Here we show that corticosteroids affect murine
macrophages by inhibiting the production of IL-12, a cytokine that is
extremely potent in enhancing IFN- and inhibiting IL-4 synthesis in
T cells (13, 14). The reduced production of IL-12 by
corticosteroid-treated macrophages resulted in a decreased ability to
induce IFN- and an increased ability to induce IL-4.
These results strongly suggest that corticosteroids have the potential to enhance Th2 cytokine synthesis. Since Th2 cytokines inhibit inflammatory conditions such as diabetes and transplant rejection, such an effect may be beneficial for such inflammatory problems. However, although administration of corticosteroids may benefit acute asthma or allergic disease by directly inhibiting cytokine synthesis in T cells, enhanced production of Th2 cytokines by corticosteroid therapy may indirectly exacerbate allergic disease, which is caused by the overproduction of Th2 cytokines in allergen-specific CD4+ T cells. This deleterious effect would result from a reduction in IL-12 synthesis by corticosteroids, thereby enhancing the production of Th2 cytokines, and limiting the production of Th1 cytokines (which attenuate allergic disease).
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
DBA/2 mice or BALB/c x DBA/2 (CByD2)F1 mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and were used at 6 to 8 wk of age.
Reagents
9-Fluoro-16-methyl-prednisolone (dexamethasone, or DXM)3 was purchased from Sigma Chemical Company (St. Louis, MO).
Culture medium
Cells were cultured in DMEM (HyClone Laboratories, Logan, UT) supplemented as described previously (15) and containing 10% FCS (HyClone Laboratories, Logan, UT) cDMEM.
Immunizations
To generate primed CD4+ T cells, mice were primed with 150 µg of keyhole limpet hemocyanin (KLH, Calbiochem, San Diego, CA) in CFA in the footpads 9 days before use.
Monoclonal Abs
Monoclonal anti-Ly 2.1 (HB129),
anti-I-Ad (MKD6), anti-CD24 (TIB183), and
anti-I-Ed (14.4.4s) Ab-secreting hybridomas were
obtained from ATCC (American Type Culture Collection, Rockville, MD)
and purified from ascites fluid by ammonium sulfate precipitation.
Anti-IL-12 p40 mAbs C17.8 and C15.6 (provided by Dr. Giogio Trinchieri,
Wistar Institute of Anatomy and Biology, Philadelphia, PA), monoclonal
anti-IFN- Abs R4–6A2 (ATCC) and XMG1.2 (obtained from Dr. Tim
Mosmann, University of Manitoba, Edmonton, Canada), monoclonal
anti-IL-10 Abs JES-2A5 and SXC.1 (Dr. M. Howard, DNAX Research
Institute, Palo Alto, CA), and monoclonal anti-IL-4 Abs BVD4–1D11
and BVD6–24G2 (Dr. M. Howard, DNAX) were purified from ascites fluid
by ammonium sulfate precipitation followed by DEAE-Sephacel
chromatography (Sigma).
Lymphokines
Recombinant murine IL-12 was generously provided by Dr. Stanley
Wolf (Genetics Institute, Cambridge, MA). Recombinant murine IL-4 was a
generous gift of Dr. M. Howard (DNAX). Recombinant murine IFN- was
provided by Dr. M. Palladino, Genentech (San Francisco, CA).
Preparation of splenic adherent cells (SpAC)
Spleen cells were cultured at 106/ml in cDMEM medium in tissue culture dishes (Falcon 3003; Becton Dickinson, Mountain View, CA) for 2 to 3 h at 37°C. The nonadherent cells were removed by washing with warm cDMEM until visual inspection revealed a lack of lymphocytes (>98% of the cell population). The adherent cells were removed from plates by incubating for 15 min with ice-cold PBS and rinsing repeatedly.
Stimulation of SpAC with heat-killed Listeria monocytogenes (HKL) or LPS
The isolated SpAC population was stimulated in the presence or absence of DXM at 10-6, 10-7, 10-8, and 10-9 M at 1 x 105 per well in 96-well culture plates with either 50 µg/ml of LPS or with HKL at 2 x 106 bacteria per well, prepared as previously described (16). Supernatants were collected after 18 h and analyzed for IL-12 content. In some experiments, the SpAC were incubated overnight in media in the presence or absence of DXM, then washed with warm cDMEM three times to remove DXM before addition of HKL, LPS, or CD4+ T cells. Supernatants were collected after 18 h and assayed for cytokine content by ELISA.
Purification of CD4+ T cells
Draining axillary, popliteal, and inguinal lymph nodes were removed from mice 9 days after priming with KLH in CFA in the footpads. Lymphocytes were depleted of B cells by adherence to goat anti-mouse Ig-coated dishes for 1 h at 4°C. Nonadherent cells were depleted of CD8+ T cells, residual B cells, and other accessory cells by treating the cells with a mixture of anti-CD8, anti-class II, anti-CD24 mAbs on ice for 10 min, followed by addition of baby rabbit C' (Pel Freeze, Rogers, AR) and incubation at 37°C for 45 min.
Induction of cytokine synthesis in CD4+ T cells
Purified CD4+ T cells were incubated in 96-well
plates at 4 x 105/well with SpAC and KLH (10 µg/ml)
in 0.15 ml of cDMEM in quadruplicate. Culture supernatants were
harvested on day 2 or 4 as indicated and assayed for levels of IL-4,
IL-10, IL-12, and IFN- by ELISA. In some experiments, T cells were
recovered after 4 days of culture and stimulated at 4 x
105/well with fresh normal SpAc (105/well) and
Ag (KLH, 10 µg/ml). Supernatants were harvested at 24 h after
restimulation.
Cytokine ELISA
Cytokine content in supernatants was determined by ELISA. In
brief, 96-well plates were coated overnight with primary
anti-cytokine capture Ab. Plates were washed, blocked, and
dilutions of supernatants or standards were added. Dilutions of culture
supernatant were incubated overnight at 4°C, and after washing, the
wells were incubated with biotin-conjugated anti-cytokine-detecting
mAb. After a 2-h incubation, the plates were washed and a horseradish
peroxidase-streptavidin conjugate (Southern Biotechnology Associates,
Inc., Birmingham, AL) was added. The plates were incubated for an
additional hour, and after washing, O-phenyldiamine (OPD) substrate was
added. After developing, the OD was determined at 492 nm. The amount of
cytokine in each supernatant was extrapolated from the standard curve.
The Ab pairs used were as follows, listed by capture/biotinylated
detection: IL-4, BVD4–1D11/BVD6–24G2; IFN-, R4–6A2/XMG1.2; IL-12,
C17.8/C15.6. The standards were cytokine curves generated in 1:2
dilutions from 500 to 39 pg/ml for IL-4, 20 to 0.156 ng/ml for IFN-,
and 4000 to 30 pg/ml for IL-12. Standards for IL-4, IL-10, and IFN-
are culture supernatants of Th2 or Th1 clones generated in our lab,
which were calibrated against recombinant cytokines. The IL-12 standard
used was a culture supernatant of SpAC stimulated with HKL, which
was calibrated against rIL-12.
Lymphokine assays
IL-2 was assayed by using the T cell growth factor-dependent line HT2 (generously provided by Dr. Sam Strober, Stanford University, Palo Alto, CA). HT2 cells (5 x 103/well) were added to dilutions of test samples in 96-well plates. Differential blocking of IL-4 or IL-2 was achieved by adding the anti-IL-4 mAb 11B11, or the anti-IL-2 mAb S4B6, or both. Test samples were diluted such that the mAbs were present in excess, as demonstrated by complete inhibition of HT2 proliferation in the presence of both mAbs. After 18 h, cells were pulsed with 1 mCi of [3H]thymidine for 4 h. Cultures were harvested with a PHD harvester (Cambridge Technology, Cambridge, MA) and [3H]thymidine was measured using standard liquid scintillation counting techniques. Units of IL-2 present in culture supernatants were calculated using recombinant murine IL-2 as a standard.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Previous studies demonstrated that DXM acts directly on T cells to
inhibit cytokine production. We wished to determine whether DXM could
also influence T cell cytokine synthesis indirectly via an effect on
IL-12 production by APCs. SpAC were isolated from naive DBA/2 mice and
incubated with HKL or LPS for 24 or 48 h in the presence or
absence of DXM. Figure 1
shows that SpAC
produced large quantities of IL-12 when cultured with HKL or LPS, and
that such IL-12 production was greatly inhibited by the presence of
DXM. The inhibition of IL-12 synthesis was dose dependent over a wide
range of DXM concentrations, and occurred when the adherent cells were
stimulated with either HKL or LPS. Furthermore, the reduction in IL-12
synthesis occurred both in cultures in which DXM remained and in those
in which DXM was washed out after 6 to 8 h of pretreatment of
monocytes with DXM before stimulation with Listeria (Fig. 2).
|
|
and enhances their capacity to induce IL-4 production by
T cells
Since IL-12 has been shown to have potent effects on cytokine
production by CD4+ T cells, we asked if the cytokine
profiles of CD4+ T cells responding to Ag presented by
DXM-pretreated APC would be altered. Direct effects of DXM on T cells
were eliminated by pretreatment of SpAC from naive DBA/2 in vitro with
DXM for 18 h and washing them to remove DXM, before culture with
syngeneic CD4+ T cells purified from lymph nodes of
KLH-primed mice and the Ag KLH. Figure 3A shows that IL-12 production
in cultures of DXM-pretreated SpAC was significantly decreased in
comparison with untreated SpAC. In the absence of DXM treatment,
stimulation with KLH resulted in the development of T cells producing
high levels of IFN-. However, pretreatment of SpAC with DXM for
18 h greatly inhibited their capacity to induce the development of
IFN- production by T cells (Fig. 3B) and
significantly increased production of IL-4 (Fig. 3C).
DXM-pretreated APC induced robust amounts of IL-4 and IL-5 in purified
T cells, indicating that these cells are viable. No cytokine production
by T cells was detected in the absence of APC, demonstrating that the
DXM-treated APC are inducing the cytokine production. Thus,
pretreatment of monocytes with DXM enhances their capacity to
preferentially induce Th2 and inhibit Th1 cytokine synthesis.
|
production by
T cells
SpACs pretreated with DXM developed an increased capacity to
induce another Th2 cytokine, IL-5 (Fig. 4A), and a reduced
capacity to induce IL-2 (Fig. 4B). In these
experiments, CD4+ T cells were purified from lymph nodes of
KLH-primed mice and cultured with DXM-pretreated SpAC or control SpAC
in the presence of the Ag KLH. T cells stimulated with control APC
produced very low levels of IL-5 in the initial culture, while T cells
stimulated with DXM-pretreated SpAC produced much greater quantities of
IL-5. Moreover, the change in cytokine profile induced by
DXM-pretreated SpAC was made more pronounced when the T cells in the
initial culture were restimulated after 4 days with normal APC and KLH
(Fig. 4). These results indicate that T cells stimulated with
DXM-treated SpAC and Ag become committed to a Th2 pattern of cytokine
synthesis.
|
To determine whether the diminished capacity of DXM-pretreated
SpAC to induce IFN- synthesis in T cells was a result of their
diminished production of IL-12, we reconstituted cultures of
DXM-pretreated monocytes and T cells with rIL-12. In cultures of primed
T cells and untreated SpAC, IFN- production is stimulated by
endogenous production of IL-12 since addition of anti-IL-12 Ab
blocks production of IL-12 (Ref. 17, and data not shown). Figure 5 shows that addition of 5 or 1 pg/ml of
IL-12 to cultures of DXM-pretreated SpAC and T cells greatly reduced
IL-4 production and enhanced IFN- production in these cultures to
levels seen in control cultures. These results suggest that reduction
of IL-12 synthesis by DXM-treated monocytes was a major effect that
determined the capacity of monocytes to regulate cytokine synthesis in
T cells.
|
To demonstrate that DXM had a consequential effect on APCs in an
in vivo setting, mice were injected with a therapeutic dose of DXM (100
µg i.p.). After 24 h, SpAC were purified from the DXM-pretreated
mice, or from control injected mice. Figure 6 shows that SpAC from DXM-pretreated
mice produced much lower amounts of IL-12 in response to either HKL or
LPS than SpAC from control mice. To determine whether proliferation or
cytokine production by Ag-primed T cells would differ in the presence
of Ag presented by SpAC from mice treated in vivo with DXM, SpAC were
purified from DBA/2 mice 24 h following i.p. injection of DXM (100
µg), and cultured with CD4+ T cells from KLH-primed mice,
and KLH. Figure 7 demonstrates that
proliferation of KLH-primed T cells was greatly reduced when stimulated
with Ag and SpAC from DXM-treated animals compared with SpAC from
control mice. Production of IL-12 in cultures containing T cells and
SpAC from DXM-treated mice was also reduced. Moreover, SpAC from
animals injected with DXM induced significantly lower amounts of
IFN- and greater amounts of IL-4 than SpAC from control mice. These
results show that in vivo treatment with DXM alters the capacity of APC
to induce IFN- and IL-4.
|
|
A
shows that IL-12 production by SpAC was still significantly reduced
from that of control 3 days after injection. However, by 7 days after
injection of DXM, IL-12 production by SpAC returned to levels
comparable to that seen in untreated mice (Fig. 8B).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and IL-2 in
CD4+ T cells. Moreover, SpAC pretreated in vivo with
DXM, by i.p. injection of mice with DXM, were similar to in vitro
DXM-pretreated SpAC in producing significantly reduced levels of IL-12.
These results demonstrate that corticosteroids can enhance the
production of IL-4 in T cells indirectly via effects on APC, and help
to resolve conflicting data generated in different laboratories
regarding the effects of corticosteroids on cytokine production,
particularly of IL-4 in CD4+ T cells.
Previous studies have shown that corticosteroids could either inhibit
or enhance IL-4 synthesis in T cells. Corticosteroids inhibited the
transcription of multiple cytokines, including IL-4 and IFN- (18, 19), as well as TNF-
, granulocyte macrophage-CSF, IL-3, and IL-5 (2, 20, 21). The inhibition of transcription and synthesis of IL-4, IL-5,
and IFN- by corticosteroids was demonstrated in both in vivo and in
vitro studies, using both resting T cells as well as effector T cell
clones (18, 19). On the other hand, several studies showed that
corticosteroids enhance IL-4 synthesis (9, 10) and may enhance IFN-
synthesis in vivo (22). That corticosteroids have the capacity to
enhance IL-4 synthesis in T cells is consistent with the observation
that administration of corticosteroids in vivo increases IgE
synthesis (11).
The contrasting past results regarding the effects of glucocorticoids
on cytokine synthesis in different systems may be due to the fact that
glucocorticoids have a wide range of effects on intracellular
biochemistry in a variety of different cell types, including T cells
and APC. Glucocorticoids affect cytokine synthesis in T cells by
binding to and activating cytoplasmic glucocorticoid receptors. The
receptor-corticosteroid complex then translocates to the nucleus, where
it regulates the transcription of target genes through several
mechanisms (23). First, the activated receptor complex inhibits
transcription of cytokine genes by binding to the transcription factor
AP-1 (composed of c-Fos and c-Jun), and preventing AP-1 from binding to
the promoter regions of cytokines (24, 25, 26). In addition, the activated
glucocorticoid receptor complex functions as a positive transcription
factor that increases transcription of the I-B, a protein that
blocks the translocation into the nucleus of NF-B, another potent
positive regulator of many cytokine and cell adhesion genes (5, 6).
Inhibition of transcription of cytokine genes by corticosteroids occurs
in both resting and in activated effector T cells, and therefore
corticosteroids are important in inhibiting acute disease in which
cytokine production is ongoing, as well as in functioning to prevent
the actual development of allergy-inducing effector cells.
In our cultures, DXM decreased the production of IL-12 by SpAC, and
altered their subsequent capacity to induce IL-4 and IFN- production
in T cells. The effect of corticosteroids on cytokine production in T
cells was indirect, since the T cells in these cultures were never
directly exposed to the corticosteroids. It is very unlikely that even
small amounts of contaminating DXM were present when the T cells were
added, since the pretreated adherent cells were washed extensively, and
since contaminating DXM would directly affect the T cells by inhibiting
rather than enhancing IL-4 synthesis. These results indicate that a
short incubation of SpAC with DXM can have persistent effects on the
ability of SpAC to regulate cytokine synthesis in T cells. Since we and
others have shown that the cytokine profiles of activated effector T
cells are difficult to modify (14, 27, 28), we believe that
corticosteroid-pretreated SpAC altered the cytokine profiles of
uncommitted but memory CD4+ T cells, rather than
differentially expanding a subset of T cells already committed toward
the Th2 profile (29).
Although corticosteroids may affect cytokine production in T cells in
several ways, we believe that inhibition of IL-12 production in SpAC is
a major mechanism by which corticosteroids affect cytokine synthesis
(and enhance IL-4 synthesis) in T cells, particularly since IL-12 is
extremely potent in inhibiting IL-4 and enhancing IFN- synthesis in
both unprimed as well as resting memory T cells (13, 14, 28). Although
the IL-12 determinations performed in our experiments utilized an IL-12
p40 ELISA, which does not measure the presence of the IL-12 p35 chain,
in studies in which both IL-12 p40 and IL-12 p70 were measured, IL-12
p40 levels correlated directly with those of IL-12 p70, though levels
of IL-12 p70 were lower (17). The levels of IL-12 p40 correlated
directly with that of IFN-, consistent with the idea that the major
biologic effects of IL-12 are to enhance Th1 cytokine synthesis
(30).
Corticosteroids might also enhance IL-4 production in T cells by
increasing the production of IL-10 in SpAC. We have recently observed
that corticosteroids enhance IL-10 production (but decrease IL-12
production) in human peripheral blood monocytes (31), but
corticosteroid treatment did not affect IL-10 production in the murine
APC that we tested. Since reconstitution of our DXM-treated cultures
with rIL-12 reversed the effects of corticosteroids on IL-4 and IFN-
synthesis, we believe that reduction of IL-12 production in SpAC by
corticosteroids was the major immunoregulatory mechanism that occurred
in our system. IL-12 has been reported to increase IL-10 production by
T cells in systems using established T cell lines rather than resting T
cells (32), or in systems using IL-12 in the presence of anti-IL-4
mAb (33), but these effects appear to occur mainly when very high
concentrations of IL-12 (10 ng/ml, or 1000 times what was placed in our
cultures) are used.
Our observations demonstrating that pretreatment of APC with
corticosteroids inhibit IL-12 production and enhance their capacity to
induce IL-4 but not IFN- have significant clinical implications. For
example, current therapy for asthma focuses on early intervention with
inhaled corticosteroids, which eliminate pulmonary eosinophilia and
reduce Th2 cytokine synthesis by activated T cells in the lung. During
subsequent immune responses, circulating T cells that become activated
against Ag presented by resident APC that produce reduced quantities of
IL-12. Activation of such T cells in the absence of IL-12 would drive
the production of Th2 cytokines in these newly arriving T cells, but
limit synthesis of IFN-. Similar situations could arise with
systemic corticosteroid therapy, in particular because of the very
short half-life of most synthetic corticosteroids. Since we
demonstrated that in vivo exposure (as well as in vitro exposure) to
corticosteroids clearly results in a reduction of IL-12 production
(Fig. 5
), which persists for at least several days, a short burst of
systemic corticosteroid therapy is likely to reduce the capacity of APC
to produce IL-12 (and greatly reduce cytokine synthesis in activated
but not resting T cells). If, however, resting (cytokine-uncommitted) T
cells are subsequently activated by APC preexposed to corticosteroids,
enhanced IL-4 production but limited IFN- synthesis would be
induced. Although therapy for autoimmune inflammatory disease or solid
organ transplant rejection may benefit by such enhanced IL-4 production
in CD4+ T cells, the long-term course of allergic diseases
may be negatively affected by intermittent or chronic inhaled
corticosteroid therapy that enhances Th2 cytokine synthesis. In the
allergic patient with chronic disease, the effect would be insidious
and difficult to detect, since T cells in allergic individuals are
already predisposed toward the production of Th2 cytokines, and since
the immediate inhibitory effects of corticosteroids on eosinophilic
inflammation are so dramatic.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. R. H. DeKruyff, Department of Pediatrics, Room S303, Stanford University, Stanford, CA 94305-5119.
3 Abbreviations used in this paper: DXM, dexamethasone; KLH, keyhole limpet hemocyanin; SpAC, splenic adherent cells; HKL, heat killed Listeria monocytogenes; cDMEM, complete DMEM.
Received for publication May 16, 1997. Accepted for publication November 17, 1997.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-interferon messenger RNA. J. Immunol. 133:273.[Abstract]
B in mediation of immunosuppression by glucocorticoids. Science 270:283.B activity through induction of IB synthesis. Science 270:286. synthesis in primed CD4 lymphocytes. Int. Immunol. 8:1511.B and the glucocorticoid receptor. Proc. Natl. Acad. Sci. USA 91:752. (IFN-) production during differentiation of human T helper (Th) cells and transient IFN- production in established Th2 cell clones. J. Exp. Med. 179:1273.. J. Immunol. 157:1127.[Abstract]
This article has been cited by other articles:
|
|
 |
|
  N.-n. Shan, X.-j. Zhu, Q. Wang, C.-y. Wang, P. Qin, J. Peng, and M. Hou High-dose dexamethasone regulates interleukin-18 and interleukin-18 binding protein in idiopathic thrombocytopenic purpura Haematologica, November 1, 2009; 94(11): 1603 - 1607. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Villalta, H. X. Nguyen, B. Deng, T. Gotoh, and J. G. Tidball Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy Hum. Mol. Genet., February 1, 2009; 18(3): 482 - 496. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhang, K. Alekseev, K. Jung, A. Vlasova, N. Hadya, and L. J. Saif Cytokine Responses in Porcine Respiratory Coronavirus-Infected Pigs Treated with Corticosteroids as a Model for Severe Acute Respiratory Syndrome J. Virol., May 1, 2008; 82(9): 4420 - 4428. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kern and T. Ziemssen Review: Brain immune communication psychoneuroimmunology of multiple sclerosis Multiple Sclerosis, January 1, 2008; 14(1): 6 - 21. [Abstract] [PDF]
|
|
|
|
 |
|
 H. S. Bandukwala, B. S. Clay, J. Tong, P. D. Mody, J. L. Cannon, R. A. Shilling, J. S. Verbeek, J. V. Weinstock, J. Solway, and A. I. Sperling Signaling through Fc{gamma}RIII is required for optimal T helper type (Th)2 responses and Th2-mediated airway inflammation J. Exp. Med., August 6, 2007; 204(8): 1875 - 1889. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Salak-Johnson and J. J. McGlone Making sense of apparently conflicting data: Stress and immunity in swine and cattle J Anim Sci, March 1, 2007; 85(13_suppl): E81 - E88. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wada, R. Lu, D. Zhou, J. Chu, T. Przewloka, S. Zhang, L. Li, Y. Wu, J. Qin, V. Balasubramanyam, et al. Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor Blood, February 1, 2007; 109(3): 1156 - 1164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Fahey, R. A. Robins, K. B. Kindle, D. M. Heery, and C. S. Constantinescu Effects of glucocorticoids on STAT4 activation in human T cells are stimulus-dependent J. Leukoc. Biol., July 1, 2006; 80(1): 133 - 144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Cannarile, F. Fallarino, M. Agostini, S. Cuzzocrea, E. Mazzon, C. Vacca, T. Genovese, G. Migliorati, E. Ayroldi, and C. Riccardi Increased GILZ expression in transgenic mice up-regulates Th-2 lymphokines Blood, February 1, 2006; 107(3): 1039 - 1047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. N. Georas, J. Guo, U. De Fanis, and V. Casolaro T-helper cell type-2 regulation in allergic disease Eur. Respir. J., December 1, 2005; 26(6): 1119 - 1137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Stock, O. Akbari, R. H. DeKruyff, and D. T. Umetsu Respiratory Tolerance Is Inhibited by the Administration of Corticosteroids J. Immunol., December 1, 2005; 175(11): 7380 - 7387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dorsch, Y. Qiu, D. Soler, N. Frank, T. Duong, A. Goodearl, S. O'Neil, J. Lora, and C. C. Fraser PK1/EG-VEGF induces monocyte differentiation and activation J. Leukoc. Biol., August 1, 2005; 78(2): 426 - 434. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-i. Seino, T. Yamauchi, K. Shikata, S. Kobayashi, M. Nagai, M. Taniguchi, and K. Fukao Prevention of acute and chronic allograft rejection by a novel retinoic acid receptor-{alpha}-selective agonist Int. Immunol., May 1, 2004; 16(5): 665 - 673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Wiley, M. Cwiartka, D. Alvarez, D. C. Mackenzie, J. R. Johnson, S. Goncharova, L. Lundblad, and M. Jordana Transient Corticosteroid Treatment Permanently Amplifies the Th2 Response in a Murine Model of Asthma J. Immunol., April 15, 2004; 172(8): 4995 - 5005. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. D. Thullen, A. D. Ashbaugh, K. R. Daly, M. J. Linke, P. E. Steele, and P. D. Walzer Sensitized Splenocytes Result in Deleterious Cytokine Cascade and Hyperinflammatory Response in Rats with Pneumocystis Pneumonia despite the Presence of Corticosteroids Infect. Immun., February 1, 2004; 72(2): 757 - 765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Ma, K. Gee, W. Lim, K. Chambers, J. B. Angel, M. Kozlowski, and A. Kumar Dexamethasone Inhibits IL-12p40 Production in Lipopolysaccharide-Stimulated Human Monocytic Cells by Down-Regulating the Activity of c-Jun N-Terminal Kinase, the Activation Protein-1, and NF-{kappa}B Transcription Factors J. Immunol., January 1, 2004; 172(1): 318 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Z. Rofael, R. M. Turkall, and M. S. Abdel-Rahman Effect of Ketamine on Cocaine-Induced Immunotoxicity in Rats International Journal of Toxicology, September 1, 2003; 22(5): 343 - 358. [Abstract] [PDF]
|
|
|
|
|
|
S. L. Young, M. A. O'Donnell, and G. S. Buchan IL-2-secreting recombinant bacillus Calmette Guerin can overcome a Type 2 immune response and corticosteroid-induced immunosuppression to elicit a Type 1 immune response Int. Immunol., July 1, 2002; 14(7): 793 - 800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.C. von Hertzen Role of persistent infection in the control and severity of asthma: focus on Chlamydia pneumoniae Eur. Respir. J., March 1, 2002; 19(3): 546 - 556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. P. Stowe, D. L. Pierson, and A. D. T. Barrett Elevated Stress Hormone Levels Relate to Epstein-Barr Virus Reactivation in Astronauts Psychosom Med, November 1, 2001; 63(6): 891 - 895. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. SALVI, K. SURESH BABU, and S. T. HOLGATE Is Asthma Really Due to a Polarized T Cell Response Toward a Helper T Cell Type 2 Phenotype? Am. J. Respir. Crit. Care Med., October 15, 2001; 164(8): 1343 - 1346. [Full Text] [PDF]
|
|
|
|
|
|
D. Little, S. Khanolkar-Young, A. Coulthart, S. Suneetha, and D. N. J. Lockwood Immunohistochemical Analysis of Cellular Infiltrate and Gamma Interferon, Interleukin-12, and Inducible Nitric Oxide Synthase Expression in Leprosy Type 1 (Reversal) Reactions before and during Prednisolone Treatment Infect. Immun., May 1, 2001; 69(5): 3413 - 3417. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Van Laethem, E. Baus, L. A. Smyth, F. Andris, F. Bex, J. Urbain, D. Kioussis, and O. Leo Glucocorticoids Attenuate T Cell Receptor Signaling J. Exp. Med., April 2, 2001; 193(7): 803 - 814. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Tang, M. D. Inman, N. van Rooijen, P. Yang, H. Shen, K. Matsumoto, and P. M. O'Byrne Th Type 1-Stimulating Activity of Lung Macrophages Inhibits Th2-Mediated Allergic Airway Inflammation by an IFN-{{gamma}}-Dependent Mechanism J. Immunol., February 1, 2001; 166(3): 1471 - 1481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Varga, P. Wachholz, K. T. Nouri-Aria, A. Verhoef, C. J. Corrigan, S. J. Till, and S. R. Durham T Cells from Human Allergen-Induced Late Asthmatic Responses Express IL-12 Receptor {beta}2 Subunit mRNA and Respond to IL-12 In Vitro J. Immunol., September 1, 2000; 165(5): 2877 - 2885. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ribas, L. H. Butterfield, B. Hu, V. B. Dissette, W. S. Meng, A. Koh, K. J. Andrews, M. Lee, S. N. Amar, J. A. Glaspy, et al. Immune Deviation and Fas-mediated Deletion Limit Antitumor Activity after Multiple Dendritic Cell Vaccinations in Mice Cancer Res., April 1, 2000; 60(8): 2218 - 2224. [Abstract] [Full Text]
|
|
|
|
|
|
K. TAMAGAWA, Y. TAOOKA, A. MAEDA, K. HIYAMA, S. ISHIOKA, and M. YAMAKIDO Inhibitory Effects of a Lecithinized Superoxide Dismutase on Bleomycin-Induced Pulmonary Fibrosis in Mice Am. J. Respir. Crit. Care Med., April 1, 2000; 161(4): 1279 - 1284. [Abstract] [Full Text]
|
|
|
|
|
|
E. Kuroda, T. Sugiura, K. Zeki, Y. Yoshida, and U. Yamashita Sensitivity Difference to the Suppressive Effect of Prostaglandin E2 Among Mouse Strains: A Possible Mechanism to Polarize Th2 Type Response in BALB/c Mice J. Immunol., March 1, 2000; 164(5): 2386 - 2395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Franchimont, J. Galon, M. Gadina, R. Visconti, Y.-J. Zhou, M. Aringer, D. M. Frucht, G. P. Chrousos, and J. J. O'Shea Inhibition of Th1 Immune Response by Glucocorticoids: Dexamethasone Selectively Inhibits IL-12-Induced Stat4 Phosphorylation in T Lymphocytes J. Immunol., February 15, 2000; 164(4): 1768 - 1774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Delgado, J. Leceta, R. P. Gomariz, and D. Ganea Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide Stimulate the Induction of Th2 Responses by Up-Regulating B7.2 Expression J. Immunol., October 1, 1999; 163(7): 3629 - 3635. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-Y. Na, B. Y. Kang, S. W. Chung, S.-J. Han, X. Ma, G. Trinchieri, S.-Y. Im, J. W. Lee, and T. S. Kim Retinoids Inhibit Interleukin-12 Production in Macrophages through Physical Associations of Retinoid X Receptor and NFkappa B J. Biol. Chem., March 19, 1999; 274(12): 7674 - 7680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Goldman, S. E. Miles, H. E. Rudloff, K. H. Palkowetz, and F. C. Schmalstieg Jr. Immunodeficiency Due to a Unique Protracted Developmental Delay in the B-Cell Lineage Clin. Vaccine Immunol., March 1, 1999; 6(2): 161 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. L. Vieira, P. Kalinski, E. A. Wierenga, M. L. Kapsenberg, and E. C. de Jong Glucocorticoids Inhibit Bioactive IL-12p70 Production by In Vitro-Generated Human Dendritic Cells Without Affecting Their T Cell Stimulatory Potential J. Immunol., November 15, 1998; 161(10): 5245 - 5251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-Y. Wu, K. Wang, J. F. McDyer, and R. A. Seder Prostaglandin E2 and Dexamethasone Inhibit IL-12 Receptor Expression and IL-12 Responsiveness J. Immunol., September 15, 1998; 161(6): 2723 - 2730. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. W. Chung, B. Y. Kang, S. H. Kim, Y. K. Pak, D. Cho, G. Trinchieri, and T. S. Kim Oxidized Low Density Lipoprotein Inhibits Interleukin-12 Production in Lipopolysaccharide-activated Mouse Macrophages via Direct Interactions between Peroxisome Proliferator-activated Receptor-gamma and Nuclear Factor-kappa B J. Biol. Chem., October 13, 2000; 275(42): 32681 - 32687. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
