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Department of Physiology and Biophysics, University of Alabama, Birmingham, AL 35294
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1ß and the Th2-derived
cytokines IL-4 and IL-13 modulated the positive effects of CD40
engagement on inflammatory mediator expression in airway epithelial
cells. Importantly, CD40 ligation enhanced the sensitivity of airway
epithelial cells to the effects of TNF- and/or IL-1ß on expression
of RANTES, MCP-1, IL-8, and VCAM-1. In contrast, neither IL-4 nor IL-13
modified the effects of CD40 engagement on the expression of RANTES,
MCP-1, IL-8, or VCAM-1; however, both IL-4 and IL-13 attenuated the
effects of CD40 cross-linking on ICAM-1 expression. Together, these
findings suggest that interactions between CD40-responsive airway
epithelial cells and CD40 ligand+ leukocytes, such as
activated T cells, eosinophils, and mast cells, modulate
asthma-associated airway inflammation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(LT) (2). Moreover, the importance of
CD40 in the regulation of immune responses is underscored by the
observation that interruption of the CD40-CD40 ligand
(CD40L)2 interaction
halts the development and progression of several autoimmune
diseases, including experimental encephalomyelitis, collagen-induced
arthritis, and lupus, as well as responses to transplantation Ags
observed in graft-vs-host disease (reviewed in Ref. 2).
CD40L is a type II transmembrane protein classified as a member of the
TNF family. It is expressed on activated CD4+ T
cells, activated CD8+ T cells, eosinophils, mast
cells, basophils, NK cells, and activated dendritic cells
(1). Airway epithelial cells form a continuous pseudostratified layer in the lung, creating a tight barrier that protects underlying tissue from the external environment. As such, airway epithelial cells have been described classically as barrier cells that are involved in homeostasis; these cells respond to a variety of environmental stimuli, resulting in the alteration of their cellular functions such as ion transport and movement of airway secretions. Recent evidence, however, suggests that airway epithelial cells might also act as immune effector cells in response to noxious endogenous or exogenous stimuli. Several studies have shown that airway epithelial cells express and secrete various immune molecules, such as lipid mediators, oxygen radicals, adhesion molecules, and a wide variety of cytokines, including chemokines (reviewed in Ref. 3). Through the expression and production of these immune molecules, the epithelium is now thought to be important in the initiation and exacerbation of inflammatory responses within the airway.
T lymphocytes play a major role in the pathogenesis of allergic airway
disease, including asthma-associated inflammation. Elevated numbers of
activated T cells have been observed in the bronchoalveolar lavage
(BAL) fluid and bronchial tissue of asthmatic patients; the majority of
these T cells are CD4+ (reviewed in Ref.
4). CD4+ T cells are categorized
into Th1 and Th2 subsets with respect to their lymphokine production.
Specifically, Th1 cells produce IL-2, TNF-ß, and IFN-
and are
important for the development of cell-mediated immunity. In contrast,
Th2 cells express IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13 and are
essential in the generation of humoral immune responses, including IgE
production, as well as in the induction of eosinophilia. Because IgE
synthesis and eosinophilia are hallmarks of allergic airway disease, it
has been postulated that asthma-associated inflammation is mediated by
a Th2 response.
Many reports have indicated that interactions between CD40 and its
ligand, CD40L, control the development of humoral and cell-mediated
immune responses. In particular, studies utilizing CD40 or CD40L
knockout mice have suggested that CD40 ligation promotes inflammatory
responses within the airway (5, 6, 7). Despite this
observation, it is unclear which resident cell type(s) of the airway is
critical in facilitating CD40-mediated airway inflammation. Because
epithelial cells have been implicated in airway inflammatory responses,
it is likely that cell-cell interactions between CD40-responsive airway
epithelial cells and leukocytes that express CD40L, including T
lymphocytes, eosinophils, and mast cells, can initiate and/or
exacerbate lung inflammation. Therefore, the present study examined the
expression of CD40 on airway epithelial cells and its role in
amplifying inflammatory responses within the lung. Results described
herein demonstrate that airway epithelial cells express CD40 and that
cross-linking of CD40 up-regulates the expression of inflammatory
mediators, including the chemokines IL-8, RANTES, and monocyte
chemoattractant protein (MCP-1) and the adhesion molecule ICAM-1.
Moreover, these results demonstrate that the proinflammatory cytokines
TNF- and IL-1ß and the Th2-derived cytokines IL-4 and IL-13
modulate the positive effects of CD40 engagement on chemokine and
adhesion molecule expression in these cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Experiments were performed with the human airway epithelial cell line 9HTEo- (tracheal; a gift from Dr. Dieter Gruenert, University of California (San Francisco, CA (8)). The 9HTEo- cell line was cultured in LHC-8 medium (Biofluids, Rockville, MD) containing 5% FCS, 1% penicillin-streptomycin, and 0.2% Fungizone. Cells were grown at 37°C in a 5% CO2 environment and on Vitrogen 100 (Collagen, Palo Alto, CA)-coated flasks; Vitrogen 100 contains collagen types I and IV.
Immunohistochemical analysis of CD40 protein expression
Lungs from BALB/c mice were excised, quick-frozen in liquid nitrogen to preserve Ag immunoreactivity, and sectioned. Frozen sections of the upper airway were then fixed in 3% formaldehyde (TEM grade, Tousimis, Rockville, MD) and rinsed in PBS, and nonspecific sites were blocked in PBS containing 1% BSA. Samples were stained with a rat anti-mouse CD40 Ab (IC-10, 10 µg/ml, PharMingen, San Diego, CA) or rat IgG (10 µg/ml, Sigma, St. Louis, MO) as a negative control for 1 h at room temperature. Samples were then rinsed in PBS and incubated with a mouse anti-rat Ig secondary conjugated to rhodamine fluorochrome (Molecular Probes, Eugene, OR) for 1 h at room temperature. Samples were then rinsed with PBS, mounted in a solution containing 0.1% p-phenylenediamine (Sigma), and analyzed via confocal microscopy.
Analysis of CD40 surface protein expression
To examine CD40 surface expression, airway epithelial cells were
cultured with TNF-, IL-1ß, IL-4, or IL-13 at the concentrations
and time points indicated. After culture, cells were lifted with HBSS
(Ca2+ and Mg2+ free)
containing 10% FCS and 0.05 M EDTA, washed twice with 1x PBS
containing 0.2% BSA, and then stained with a mouse anti-human
anti-CD40 mAb (10 µg/ml; G28.5, a gift from Dr. Randolph Noelle,
Dartmouth Medical School, Lebanon, NH) for 30 min on ice. Parallel
samples were stained with mouse IgG1
immunoglobulin (10 µg/ml,
Sigma) as an isotype-matched Ab control. After incubation, cells were
washed as above and then incubated with the secondary Ab,
FITC-conjugated goat anti-mouse F(ab')2 IgG1
(diluted 1:100, BioSource, Camarillo, CA) for 30 min on ice. Cells were
again washed as above, resuspended in 1x PBS containing 0.2% BSA, and
analyzed via flow cytometry (Becton Dickinson, FACScalibur; University
of Alabama at Birmingham Core Facility).
Analysis of IL-8, MCP-1, and RANTES protein expression
To analyze IL-8, MCP-1, and RANTES protein expression, cells
were cultured in the presence and absence of soluble CD40L (sCD40L;
mCD8hgp39, a gift from Dr. R. J. Noelle) with or without TNF-,
IL-1ß, IL-4, or IL-13 (R&D Systems, Minneapolis, MN) at the
concentrations indicated for 18 h at 37°C. After culture,
supernatants were harvested and prepared for ELISA of IL-8, MCP-1, or
RANTES protein content (BioSource); cells were harvested and counted to
account for differences in cell number. ELISAs were performed according
to the manufacturer’s protocol (limits of detection, <3 pg/ml).
Analysis of ICAM-1 and VCAM-1 surface protein expression
To analyze ICAM-1 and VCAM-1 surface protein expression, cells
were cultured in the presence and absence of sCD40L with or without
TNF-, IL-1ß, IL-4, or IL-13 (R&D Systems) at the concentrations
indicated for 18 h at 37°C. After culture, cells were harvested
and analyzed via flow cytometry as described above for CD40 detection
with the exception that mAbs directed against ICAM-1 or VCAM-1 were
utilized (R&D Systems).
Statistical analysis
Data are expressed as the mean ± SD of replicate
determinations as indicated. Statistical significance was determined by
ANOVA. p 
0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine CD40 expression in primary airway epithelial cells,
immunohistochemical analysis of BALB/c mouse lung tissue was performed.
Mouse lung tissue was utilized for this analysis due to: 1) the
difficulty in obtaining normal human lung tissue; and 2) the potential
for phenotypic changes of primary cells cultured in vitro. Therefore,
lungs from BALB/c mice were excised, quick-frozen in liquid nitrogen to
preserve Ag immunoreactivity, and sectioned. Frozen sections of the
upper airway were then stained with either a mAb directed against
murine CD40 or an appropriate negative control. As shown in Fig. 1
, epithelial cells lining the
bronchioles of the upper airway stained brightly for CD40 (Fig. 1A), whereas negative control samples displayed little
cross-reactivity (Fig. 1B).
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100% of 9HTEo- cells stained
positively for CD40 expression (Fig. 2A). The negative control
HT-29, a human intestinal epithelial cell line that does not express
CD40 (9), did not stain for CD40 (Fig. 2B). The
change in mean fluorescence intensity for 9HTEo- cells
staining positively for CD40 expression was 4-fold greater than
controls.
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,
IL-1ß, IL-4, and/or IL-13 modulated CD40 expression on airway
epithelial cells in vitro. For these experiments, 9HTEo-
cells were cultured separately with these various cytokines at
increasing concentrations, ranging from 0.1 to 100 ng/ml, and
increasing time points, ranging from 18 to 72 h. As presented in
Fig. 2
A, neither TNF- nor IL-1ß altered airway
epithelial CD40 expression at the concentrations and time points
examined. IL-4 and IL-13 also did not affect CD40 expression on airway
epithelial cells (data not shown). CD40-mediated expression of chemokines
CD40 is known to play a role in cell-cell interactions that result
in the modulation of immune responses (2). To determine
whether cross-linking CD40 on airway epithelial cells induced the
expression of chemokines, 9HTEo- cells were cultured in
the presence and absence of sCD40L and then analyzed for protein
expression of the chemokines RANTES, MCP-1, and IL-8 via ELISAs. The
9HTEo- cell line was utilized as a model airway epithelial
cell for these studies, given that 9HTEo- cells express
CD40 (Fig. 2) and can be induced to express a variety of immune
molecules, including chemokines and adhesion molecules
(10). The chemokines IL-8, RANTES, and MCP-1 were examined
in these experiments because each has been implicated in facilitating
leukocyte migration into the airway lumen during an inflammatory
response (reviewed in Ref. 11). In particular, MCP-1
mediates monocyte and basophil chemotaxis and activation whereas IL-8
primarily induces the migration of neutrophils. RANTES induces the
chemotaxis of eosinophils, monocytes, and CD45
RO+ memory T lymphocytes. The data in Fig. 3 demonstrate that CD40 ligation induces
chemokine expression in 9HTEo- cells. Specifically, sCD40L
up-regulated RANTES, IL-8, and MCP-1 expression in 9HTEo-
cells from undetectable levels to 0.6 ng/106
cells, 1.3 ng/106 cells, and 2.2
ng/106 cells, respectively (Fig. 3A).
Importantly, sCD40L induced the expression of RANTES, IL-8, and MCP-1
in a dose-dependent manner; sCD40L-induced IL-8 expression is shown in
Fig. 3B as a representative example. The effects of sCD40L
on chemokine expression in airway epithelial cells were blocked by a
mAb directed against CD40L (TRAP1, data not shown).
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The adhesion molecules ICAM-1 and VCAM-1 facilitate leukocyte
migration within the lung. Specifically, ICAM-1 binds
ß2 integrins expressed on a variety of cell
types, including lymphocytes and neutrophils, whereas VCAM-1 binds
VLA-4 found on eosinophils (reviewed in Ref. 12). To
determine whether CD40 engagement modulated expression of ICAM-1 and/or
VCAM-1 on airway epithelia, 9HTEo- cells were cultured
with or without sCD40L. Cells were then collected and analyzed for the
surface expression of ICAM-1 and VCAM-1 via flow cytometry. As observed
in Fig. 4A, 20% of
9HTEo- cells stained positively for ICAM-1 expression;
however, sCD40L enhanced basal ICAM-1 expression 3-fold. The dose
response for sCD40L-mediated induction of ICAM-1 expression is shown in
Fig. 4B. The change in mean fluorescence intensity for
CD40-mediated modulation of ICAM-1 expression in 9HTEo-
cells was 2-fold greater than the respective isotype matched
controls (data not shown). The effect of sCD40L on ICAM-1 expression in
airway epithelial cells was blocked by a mAb directed against CD40L
(TRAP1, data not shown). Fig. 4A also demonstrates that
9HTEo- cells express little or no detectable VCAM-1 on the
cell surface. Importantly, CD40 engagement on 9HTEo- cells
did not induce the expression of VCAM-1 above basal levels (Fig. 4A). Because VCAM-1 could be shed from the cell surface,
supernatants from these cultures were analyzed for the presence of
soluble VCAM-1 via ELISA; however, these analyses did not detect the
presence of soluble VCAM-1 (data not shown), suggesting that sCD40L
does not induce VCAM-1 surface expression on 9HTEo-
cells.
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In the asthmatic lung, airway epithelial cells are exposed to a
variety of soluble mediators, including proinflammatory and Th2-derived
cytokines, that alter their cellular activity and function. To examine
the effects of proinflammatory and Th2-derived cytokines on
CD40-mediated expression of the chemokines RANTES, IL-8, and MCP-1,
9HTEo- cells were cultured in the presence and absence of
sCD40L with and without the proinflammatory cytokines TNF- and
IL-1ß or the Th2-derived cytokines IL-4 and IL-13. Chemokine
expression was then monitored via ELISA. TNF- and IL-1ß were
utilized in these experiments because previous studies have
demonstrated that these cytokines are elevated during an inflammatory
response of the airway (13) and can modulate airway
epithelial expression of immune molecules (reviewed in Ref.
3). IL-4 and IL-13 were included in these experiments
because they are Th2-derived cytokines that have been reported to alter
the activity of airway epithelial cells (14, 15).
As demonstrated in Fig. 5, TNF- and/or
IL-1ß enhanced the effects of CD40 engagement on RANTES, IL-8, and
MCP-1 expression. Specifically, cells cultured with TNF- alone
expressed RANTES at 0.4 ng/106 cells; however,
TNF- synergized with sCD40L to increase RANTES expression to 2.0
ng/106 cells or 3- to 5-fold over that amount
observed with either stimulus alone (Fig. 5A). Similarly,
cells stimulated with IL-1ß alone expressed approximately 1.0
ng/106 cells; yet, IL-1ß synergized with sCD40L
to up-regulate MCP-1 expression to nearly 7.0
ng/106 cells or between 3.5- and 7-fold greater
than that observed with either stimulus alone (Fig. 5B).
Interestingly, TNF- and IL-1ß each combined with sCD40L to
up-regulate IL-8 expression in airway epithelial cells (Fig. 5C). In detail, TNF- and IL-1ß alone induced IL-8
expression from undetectable levels to 1.0
ng/106 cells and 1.0 ng/106
cells, respectively (Fig. 5C). Importantly, both TNF- and
IL-1ß combined with sCD40L in a synergistic fashion to enhance
CD40-mediated IL-8 expression to 3.7 and 3.0
ng/106 cells, respectively, or between 2- and
3-fold greater than that observed with either stimulus alone. In
contrast, neither IL-4 nor IL-13 induced RANTES, MCP-1, or IL-8
expression and, moreover, did not modulate the effects of CD40
cross-linking on chemokine expression in these cells (data not
shown).
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or IL-1ß at increasing concentrations. Alternatively, cells
were preincubated with sCD40L for varying time periods and then exposed
to TNF- or IL-1ß at a single concentration. After culture,
supernatants from these cultures were harvested and examined for IL-8,
RANTES, or MCP-1 protein expression via ELISA. As demonstrated in Fig. 6, ligation of CD40 increased the
sensitivity of 9HTEo- cells to the effects of TNF- and
IL-1ß in a dose-dependent manner with regard to IL-8 expression;
similar results were observed for the effects of TNF- on RANTES
expression and IL-1ß on MCP-1 expression (data not shown). In
contrast, priming the cells with sCD40L for 2 or 6 h before
exposure with TNF- or IL-1ß did not alter the effect of either
cytokine on IL-8 expression (Fig. 7);
similar results were observed for RANTES and MCP-1 expression (data not
shown).
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The effects of TNF- and IL-1ß as well as IL-4 and IL-13 on
CD40-mediated expression of the adhesion molecules ICAM-1 and VCAM-1 in
airway epithelial cells were examined. Although TNF- and IL-1ß
each induced the expression of ICAM-1 between 2- and 3-fold above basal
levels, neither of these stimuli modulated CD40-mediated expression of
ICAM-1 (Fig. 8A).
Interestingly, IL-4 and IL-13 increased ICAM-1 expression modestly in
these cells; however, both of these cytokines decreased CD40-mediated
ICAM-1 expression significantly (Fig. 8A). In contrast,
TNF- alone, but not IL-1ß, IL-4, or IL-13, induced expression of
VCAM-1 in airway epithelial cells (Fig. 8B). Importantly,
TNF- synergized with sCD40L to increase VCAM-1 expression between 3-
and 4-fold over that observed with either stimulus alone (Fig. 8B).
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with regard to VCAM-1
expression, 9HTEo- cells were cultured in the presence and
absence of sCD40L in combination with TNF- at increasing
concentrations. In addition, cells were preincubated with sCD40L for
varying time periods and then exposed to TNF- at a single dose.
After culture, cells were harvested and examined for VCAM-1 surface
expression via flow cytometry. ICAM-1 expression was not monitored in
these experiments because neither TNF- nor IL-1ß had a significant
effect on sCD40L-induced ICAM-1 expression in 9HTEo- cells
(Fig. 8). As demonstrated in Fig. 9A, ligation of CD40 increased
the sensitivity of 9HTEo- cells to the effects of TNF-
in a dose-dependent manner with regard to VCAM-1 expression. In
contrast, priming the cells with sCD40L for 2 or 6 h before
exposure with TNF- did not alter the effect of this cytokine on
VCAM-1 expression (Fig. 9B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and/or IL-1ß on expression of RANTES, MCP-1, IL-8,
and VCAM-1. In contrast, neither IL-4 nor IL-13 modified the effects of
CD40 engagement on the expression of RANTES, MCP-1, IL-8, or VCAM-1;
however, both IL-4 and IL-13 attenuated the effects of CD40
cross-linking on ICAM-1 expression. These findings suggest that
epithelial CD40 plays a role in airway inflammatory responses.
The epithelial barrier in the airway has two distinct surfaces, the
apical (luminal) and the basolateral (serosal) surfaces. The apical
surface is exposed to the environment directly whereas the basolateral
surface is protected from the environment through the existence of
tight junctions. Tight junctions facilitate selective transport of
materials across the epithelial barrier and dictate sequestration of
proteins made by epithelia to either the apical or the basolateral
compartment. To date, there is no conclusive evidence that CD40
demonstrates a polarized pattern expression on airway epithelial cells.
Our observations suggest that CD40 is expressed primarily on the apical
surface; however, we can detect CD40, albeit to a lesser degree, on the
basolateral surface (Fig. 1). A more definitive answer to this question
is being pursued via colocalization studies and laser confocal
microscopy. As stated in the Introduction, T lymphocytes
play a major role in the pathogenesis of allergic airway disease. In
fact, elevated numbers of activated T cells have been observed in the
BAL fluid and bronchial tissue of asthmatic patients (reviewed in Ref.
4). In light of the data presented herein, we anticipate
that T lymphocytes, which express CD40L on activation (1),
will encounter and interact with CD40 expressed on the
basolateral and/or apical surface of the airway epithelium as these
cells migrate from the circulation and into the airway lumen. The
consequences of such cell-cell interactions, be it at the apical and/or
the basolateral surface, will trigger the epithelium to express
increased amounts of chemokines and adhesion molecules and thereby
contribute to the airway inflammatory response.
Previous reports indicate that bronchial epithelial cells express CD40
(16, 17). In particular, Gormand et al. (17)
have reported that the cytokines TNF- and IFN- increased the
basal expression of CD40 on bronchial epithelial cell lines. Moreover,
their data suggest that ligation of CD40 expressed on bronchial
epithelial cell lines enhanced the expression of IL-6 and GM-CSF from
these cells; however, CD40 engagement did not alter the sensitivity of
these cells to the effects of TNF- with regard to IL-6 and GM-CSF
expression.
The data presented herein contrast with those of Gormand et al. First,
although our data also demonstrate CD40 expression in both lung tissue
and airway epithelial cell lines, such expression was not
modulated by the cytokines TNF-, IL-1ß, IL-4, or
IL-13. Second, as was similarly observed by Gormand et al., our data
demonstrate that the expression of inflammatory molecules,
including RANTES, IL-8, MCP-1, and ICAM-1, was increased on ligation of
CD40 on airway epithelial cells. Third, as stated above, our results
indicate that CD40 engagement enhances the sensitivity of airway
epithelial cells to the effects of the proinflammatory cytokines
TNF- and/or IL-1ß. Specifically, CD40 ligation enhanced the
response of the cells to TNF- with regard to the expression of IL-8,
RANTES, and VCAM-1, as well as IL-1ß, with regard to MCP-1 and IL-8
expression. Interestingly, CD40 ligation before cytokine exposure did
not prime airway epithelial cells to respond to either TNF- or
IL-1ß. Together, our results suggest that, as
CD40L+ cells migrate into the lung and cross the
epithelial barrier, ligation of epithelial CD40 will render the
epithelium more sensitive and responsive to the effects of
proinflammatory cytokines present in the local microenvironment.
In addition to airway epithelial cells, other CD40-responsive cell
types in the lung have been identified. Lazaar et al. (18)
reported that cross-linking CD40 on airway smooth muscle cells with
CD40L up-regulates the expression of the pleiotropic cytokine IL-6.
Similarly, Sempowski et al. (19) demonstrated that
cross-linking CD40 on lung fibroblasts with CD40L induces the
expression of IL-6 and the chemokine IL-8; expression of both of these
molecules was enhanced further in the presence of IFN-. Moreover,
Zhang et al. (20) reported that engagement of CD40 on lung
fibroblasts increased PGE2 synthesis via the
induction of cyclooxygenase-2.
Recent reports suggest that CD40 plays a role in airway inflammatory
responses in vivo. For example, Adawi et al. have reported that
disruption of CD40-CD40L interactions blunts hyperoxic lung injury
(21) and protects against radiation-induced pulmonary
toxicity (22). Specifically, these authors demonstrated
that mice pretreated with an Ab against CD40L protected against
oxygen-induced lung injury as well as radiation-induced pneumonitis and
fibrosis. Studies utilizing CD40 or CD40L knockout mice have also
implicated CD40 in airway inflammatory responses in vivo. Wiley et al.
(5) have shown that treatment of wild-type CD40 mice with
sCD40L increased polymorphonuclear cell infiltration of the alveolar
space and an accumulation of alveolar macrophages with increased Ia
expression; such an increase in cell infiltration of the lungs was not
observed in CD40L-treated CD40 knockout mice. Similarly, Lei et al.
(7) have reported altered airway immune responses in CD40L
knockout mice. These authors observed that CD40L knockout mice
sensitized with OVA followed by an OVA aerosol challenge, as a model of
allergic airway inflammation, displayed a reduced airway inflammatory
response when compared with similarly sensitized and challenged
wild-type controls. Specifically, significantly less numbers of
monocytes, lymphocytes, neutrophils, and eosinophils were detected in
the BAL fluid of CD40L knockout at 72 h postchallenge as compared
with controls. Moreover, decreased serum levels of OVA-specific IgE and
IgG1 and IL-4 and decreased BAL levels of IL-4 and TNF- were
detected in the CD40L knockout mice as compared with wild-type
controls; however, similar levels of IL-5 were detected in the serum
and BAL fluid of both control and knockout mice. In addition, lung
endothelial cell expression of VCAM-1 in OVA-sensitized and challenged
CD40L knockout mice was reduced as compared with controls.
It is evident that CD40 plays a role in lung inflammation in vivo. Identifying the CD40-responsive cells within the airway that promote inflammation is critical in understanding the mechanisms that underlie airway inflammation and, moreover, in generating novel therapies that ameliorate inflammatory diseases such as asthma.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: CD40L, CD40 ligand, MCP-1, monocyte chemoattractant protein; BAL, bronchoalveolar lavage; sCD40L, soluble CD40L.
Received for publication December 21, 1999. Accepted for publication June 5, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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M. Richter, A. M. Cantin, C. Beaulieu, A. Cloutier, and P. Larivee Zinc chelators inhibit eotaxin, RANTES, and MCP-1 production in stimulated human airway epithelium and fibroblasts Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L719 - L729. [Abstract] [Full Text] [PDF]
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Z. Zhao, Y. Qian, D. Wald, Y.-F. Xia, J.-G. Geng, and X. Li IFN Regulatory Factor-1 Is Required for the Up-Regulation of the CD40-NF-{kappa}B Activator 1 Axis During Airway Inflammation J. Immunol., June 1, 2003; 170(11): 5674 - 5680. [Abstract] [Full Text] [PDF]
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S. Kurosawa, A. C. Myers, L. Chen, S. Wang, J. Ni, J. R. Plitt, N. M. Heller, B. S. Bochner, and R. P. Schleimer Expression of the Costimulatory Molecule B7-H2 (Inducible Costimulator Ligand) by Human Airway Epithelial Cells Am. J. Respir. Cell Mol. Biol., May 1, 2003; 28(5): 563 - 573. [Abstract] [Full Text] [PDF]
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 S. M. Propst, K. Estell, and L. M. Schwiebert CD40-mediated Activation of NF-kappa B in Airway Epithelial Cells J. Biol. Chem., September 27, 2002; 277(40): 37054 - 37063. [Abstract] [Full Text] [PDF]
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N. Hizawa, E. Yamaguchi, S. Konno, Y. Tanino, E. Jinushi, and M. Nishimura A Functional Polymorphism in the RANTES Gene Promoter Is Associated with the Development of Late-Onset Asthma Am. J. Respir. Crit. Care Med., September 1, 2002; 166(5): 686 - 690. [Abstract] [Full Text] [PDF]
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