Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, California 94305-5236
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ABSTRACT |
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In 16HBE transformed human bronchial
epithelial cells, histamine stimulated interleukin (IL)-8 mRNA and
protein secretion, and this histamine stimulation was inhibited by the
H1-receptor antagonist diphenhydramine (DPH), by the
inhibitor of 5-lipoxygenase-activating protein (FLAP) MK-886, by the
5-lipoxygenase inhibitor Zileuton, and by dexamethasone. Histamine
stimulated bronchial epithelial cell production of leukotriene
B4
(LTB4), and this production was
inhibited by FLAP inhibitors MK-886 and L-655,238 and Zileuton. Histamine stimulated IL-8 luciferase reporter gene activity that was
inhibited with DPH, dexamethasone, MK-886 and L-655,238, and Zileuton.
The inhibition of IL-8 transcription and protein secretion by FLAP
inhibitors and Zileuton was reversed with exogenous
LTB4. There was increased IL-8
nuclear factor-B (NF-
B) DNA-binding activity after histamine
stimulation, and this was inhibited by DPH and MK-886. Cytoplasmic
phospholipase A2 mRNA levels were also potently induced by histamine. Thus histamine stimulation of
bronchial epithelial cells involves binding at H1
receptors, production of LTB4,
activation of NF-
B and increased expression of IL-8.
inflammation; cytokine; transcription; Zileuton; phospholipase
A2; nuclear factor-B; interleukin-8
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INTRODUCTION |
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BRONCHIAL EPITHELIAL CELLS are capable of expressing a
multitude of signaling cytokines (reviewed in Refs. 27 and 29), including interleukin (IL)-8, IL-6, tumor necrosis factor-
(TNF-
), IL-1
, and hematopoietic growth factors
granulocyte-macrophage colony-stimulating factor, granulocyte
colony-stimulating factor, colony-stimulating factor-1, IL-2 (1), and
stem cell factor (33). These factors contribute to the development of a
local immune response in the microenvironment of the airways,
appropriate for host defense against foreign pathogens. However,
excessive cytokine expression by bronchial epithelial cells likely
contributes to inappropriate proliferation and activation of immune
effector cells (8) and the cellular airway inflammation, which is a cardinal feature of asthma (27, 29).
IL-8 is a potent cytokine promoting the chemoattraction, proliferation,
and activation of neutrophils (16, 21). IL-8 is expressed by a variety
of cell types, including macrophages, neutrophils, lymphocytes, and
epithelial and endothelial cells. The regulation of IL-8 expression
involves transcriptional and posttranscriptional mechanisms and differs
significantly between cell types (21). Epithelial and endothelial cells
are capable of prompt and substantial expression of IL-8, and this
induction is primarily at the level of transcription (21, 23). The
critical transcription factor controlling the expression of IL-8 in
epithelial and endothelial cells has been shown to be nuclear factor
(NF)-B (22). IL-8 expression in lung epithelial cells has been shown
to be triggered by histamine (5) and also by the inflammatory cytokines
TNF-
and IL-1
(25, 31).
Histamine, released from mast cells in the lung, can exert proinflammatory and bronchoconstrictive effects and contribute to airway inflammation (4).
Leukotriene B4
(LTB4) has been shown to be
produced by resting bronchial epithelial cells, and production of
LTB4 is increased by inflammatory
stimuli (14, 15, 24). Bronchial epithelial LTB4 acts as a powerful
chemoattractant for leukocytes through mechanisms that involve
upregulation of cell surface integrins (reviewed in Ref.
11). Neutrophils and macrophages, recruited to and
activated at sites of inflammation, also produce
LTB4. LTB4 synthesis involves lipid
peroxidation by 5-lipoxygenase, and this process can generate reactive
oxygen intermediates (20). The transcription factor NF-B, implicated
in the regulation of numerous inflammatory cytokines (3), may be
activated by reactive oxygen intermediates (28). Brach et al. (6)
showed that LTB4 caused
transcriptional activation of IL-6 in monocytes, acting through
transcription factors NF-IL-6 and NF-
B (6). Los et al. (20) analyzed
the role of arachidonic acid metabolites involved in T cell activation
through the CD28 receptor, and they identified an important role for
5-lipoxygenase, LTB4, and reactive
oxygen intermediates in the enhancement of NF-
B DNA-binding activity and the transcriptional activation of IL-2.
Here, we have characterized an inflammatory signaling pathway in human
bronchial epithelial cells that involves histamine acting upon
H1 receptors, synthesis of
LTB4, induction of transcription factor IL-8 NF-B, and enhancement of IL-8 transcription and IL-8 protein secretion.
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MATERIALS AND METHODS |
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Cell culture. An SV40 large T
antigen-transformed human airway epithelial cell line, 16HBE14o
(16HBE), that retains differentiated morphology and function of normal
human airway epithelia (7) was from the laboratory of D. Gruenert
(University of California, San Francisco, CA). The transformed cells
were cultured in Eagle's minimum essential medium (BioWhittaker,
Walkersville, MD) supplemented with 10% heat-inactivated fetal bovine
serum, 100 U/ml penicillin, and 100 mg/ml streptomycin (BioWhittaker).
Cell stimulation and drug treatments.
Monolayer epithelial cells grown to 80% confluency were stimulated for
indicated times in culture medium containing various combinations of
stimulants, including histamine (Sigma, St. Louis, MO), recombinant
human TNF- (Biosource, Camarillo, CA), recombinant human IL-1
(PharMingen, San Diego, CA), and
LTB4 (Calbiochem). Diphenhydramine
(DPH) and cimetidine (Cim; Sigma) were used to examine histamine
H1- and H2-receptor subtypes in bronchial
epithelial cells. The following drug modulators of histamine-stimulated
IL-8 gene expression were investigated: dexamethasone (Dex; Sigma), the
5-lipoxygenase-activating protein (FLAP) inhibitors (10)
MK-886 (Calbiochem) and L-655,238 (Calbiochem), the
5-lipoxygenase inhibitor Zileuton (gift of Abbott, Abbott
Park, IL; see Ref. 13), 3-isobutyl-1-methylxanthine (IBMX; Calbiochem),
and cyclosporin A (Sandoz Research Institute, East Hanover, NJ).
Quantification of IL-8 protein and LTB4. IL-8 protein concentrations in culture supernatants of transformed human bronchial epithelial cells were measured using a human IL-8 sandwich enzyme-linked immunosorbent assay (ELISA) kit (Immunotech, Westbrook, ME). LTB4 concentrations in 16HBE culture supernatants were measured using a competitive human LTB4 enzyme immunoassay system (Amersham, Arlington Heights, IL). The assays were done following the instructions of the manufacturers and were measured in triplicate.
RNA isolation and analysis by reverse transcription-polymerase chain reaction. After stimulation, adherent epithelial cells were harvested by trypsinization, and total RNA was extracted using guanidinium isothiocyanate (RNAzol; Tel-Test, Friendswood, TX). Two micrograms of total RNA were used for reverse transcription (RT)-polymerase chain reaction (PCR) as described (1). Oligonucleotide primers for human IL-8, ![]() |
RESULTS |
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Histamine induction and drug sensitivity
of IL-8 mRNA and protein expression in 16HBE
cells. 16HBE cells are SV40-immortalized tracheobronchial epithelial cells (7). The induction of IL-8 mRNA
in 16HBE cells was analyzed by RT-PCR (Fig.
1A).
For every RT-PCR experiment we performed, we optimized the number of
cycles of PCR amplification to avoid saturation of the PCR products
generated (Fig. 1B). The RT-PCR
analysis of IL-8 mRNA induction shown in Fig.
1A was performed at 28 cycles of PCR
amplification, which is within the linear range of PCR quantitation, as
shown in Fig. 1B. In resting 16HBE
cells, there was constitutive IL-8 mRNA detectable. Histamine induced a
significant increase in IL-8 mRNA; for comparison, the stronger
induction with the potent proinflammatory cytokines TNF- and IL-1
is also shown. Histamine induction of IL-8 mRNA was inhibited by the
H1-receptor antagonist DPH but not by the H2-receptor antagonist Cim. Additionally, the FLAP
inhibitor MK-886 (10) inhibited histamine induction of IL-8 mRNA. IBMX,
a phosphodiesterase inhibitor, showed no inhibition, and cyclosporin A
showed partial inhibition of histamine-induced IL-8 mRNA. The most
potent inhibitor of IL-8 mRNA induction was Dex.
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When assayed by ELISA, histamine produced a significant increase in secreted IL-8 protein compared with nonstimulated bronchial epithelial cells (P < 0.01; Fig. 1C). There was also statistically significant inhibition of histamine-induced IL-8 secretion by DPH and Dex (P < 0.01) and by MK-886 (P < 0.05).
Transcriptional activation and drug sensitivity of the
IL-8 gene in 16HBE cells. A stably transfected
bronchial epithelial cell line was generated (16HBE/IL-8 luciferase) in
which the IL-8 enhancer and promoter drive the expression of firefly
luciferase gene. This transgenic bronchial epithelial cell line was
used to compare the inflammatory stimulants histamine, TNF-, and
IL-1
and to evaluate the effects of immunomodulating drugs on IL-8 transcription (Fig.
2A).
The results generated with the stably transfected 16HBE/IL-8 luciferase
bronchial epithelial cell line were replicated in transient
transfections. Histamine triggered a significant increase in IL-8
luciferase activity; for comparison, the more potent stimulation by
IL-1
and TNF-
is shown (Fig. 2A). Histamine caused a
dose-dependent increase in bronchial epithelial cell IL-8 luciferase
expression (Fig. 2B), and the
induction at 2 mM histamine was statistically significant
(P < 0.05). Histamine at doses up to
10 mM did not induce any measurable adverse effects on the 16HBE/IL-8
luciferase cells; there were no significant changes in cell viability
measured by trypan blue exclusion or in protein concentrations of whole
cell extracts (data not shown). The histamine H1-receptor
antagonist DPH (1 µM) caused a 30% inhibition in IL-8 luciferase
activity, whereas the H2-receptor-antagonist Cim showed
no inhibition at any concentration. At increasing doses of DPH, the
inhibitory effect on histamine signaling was lost (Fig.
2C), suggesting that DPH might be
acting as a partial agonist. These results imply that histamine
activation of IL-8 transcription in bronchial epithelial cells involves
the H1-receptor subtype.
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LTB4 production by histamine-stimulated 16HBE cells was inhibited by FLAP inhibitors and Zileuton. Nonstimulated 16HBE cells expressed no LTB4 into the culture supernatant (Fig. 3). Stimulation with histamine caused generation of detectable LTB4 in the culture supernatants (24 pg/ml; Fig. 3), and there was partial inhibition of LTB4 secretion with the FLAP inhibitors MK-886 and L-655,238 and potent inhibition with the 5-lipoxygenase inhibitor Zileuton.
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LTB4 stimulated IL-8 transcriptional activation and protein secretion. Exogenous LTB4 measured in 16HBE/IL-8 luciferase cells was discovered to be a potent stimulator of IL-8 transcriptional activation (Fig. 4A). There was significant induction with 10 nM LTB4, and the activation induced with 100 nM LTB4 was greater than that with 2 mM histamine (compare Figs. 4A and 2B). In addition, stimulation for 6 h with exogenous LTB4 caused a dose-dependent increase in secreted IL-8 protein (Fig. 4B).
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Inhibition of histamine-stimulated IL-8 transcription and protein secretion by FLAP inhibitors and Zileuton was rescued with exogenous LTB4. The FLAP inhibitors MK-886 and L-655,238 (10) and the 5-lipoxygenase inhibitor Zileuton (13) each showed a dose-dependent inhibition of histamine-stimulated IL-8 luciferase activity (Fig. 4C). These results implicate FLAP and 5-lipoxygenase in histamine signaling, leading to IL-8 transcriptional activation. For each drug inhibitor, the ability of exogenous LTB4 (10 nM) to rescue IL-8 transcriptional activation was tested. It is evident that exogenous LTB4 was able to rescue the inhibition of histamine-stimulated IL-8 transcriptional activation caused by MK-886, by L-655,238, and also by Zileuton (Fig. 4C). In addition, in Fig. 4D we show that that Zileuton completely inhibited the effects of histamine stimulation on IL-8 protein secretion, and this Zileuton inhibition was reversed with exogenous LTB4. These results implicate LTB4 as an intracellular messenger molecule that acts downstream in the signaling pathway from the histamine H1 receptor, from FLAP, and from 5-lipoxygenase.
Induction and drug sensitivity of transcription factor IL-8 NF-
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Histamine potently induced cPLA2 mRNA in
16HBE cells.
cPLA2 can be induced by
inflammatory stimuli (reviewed in Ref. 34). Figure
6 showns the induction of
cPLA2 mRNA after stimulation with
TNF-, IL-1
, or histamine. It is apparent that histamine was the
most potent stimulant for the induction of
cPLA2 mRNA, and this induction was
inhibited by DPH, MK-886, and Dex.
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DISCUSSION |
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We have shown that histamine activates bronchial epithelial
cell signaling pathways that involve synthesis of
LTB4 and transcriptional activation of NF-B, leading to secretion of IL-8. Histamine
induction of IL-8 expression could be inhibited with an
H1-receptor antagonist and with inhibitors of
5-lipoxygenase synthetic function. The 16HBE14o
cell line that
we studied is a good model of the native epithelium, and its growth
properties allowed us to characterize signaling pathways and
transcriptional regulation that would not have been feasible using
primary cultures of bronchial epithelium.
Our in vitro studies of the ability of histamine to induce IL-8 are relevant to the pathogenesis of airway inflammation in asthma. Bellini et al. (5) demonstrated that bronchial epithelial cells recovered from asthmatic but not from normal volunteers, when stimulated with 1 µM histamine, expressed lymphocyte chemoattractant activity that was partially due to IL-8. In airway inflammation, mast cells degranulate and release histamine in close proximity to bronchial epithelial cells. In immediate hypersensitivity reactions, the tissue concentration of histamine has been estimated to reach 1 mM (30). Thus the concentrations of histamine that we required to activate IL-8 expression in 16HBE cells in vitro may be achieved in vivo under conditions of airway inflammation characteristic of asthma.
Histamine was shown to trigger the expression of inflammatory cytokines IL-6 and fibronectin from BEAS-2B bronchial epithelial cells (26). These proinflammatory effects of histamine were mediated through H1 receptors and were associated with transient increases in intracellular calcium. In guinea pig tracheal epithelial cells and in BEAS-2B cells, histamine was shown to activate H1 receptors that coupled to pertussis toxin-insensitive G proteins, leading to accumulation of inositol phosphates (19). Leurs et al. (17) showed in Chinese hamster ovary cells that transfected H1 receptor coupled to four distinct intracellular signaling pathways: 1) elevation of intracellular calcium, 2) generation of inositol phosphates, 3) potentiation of cAMP accumulation, and 4) massive release of arachidonic acid. The coupling between the H1 receptor and each intracellular signaling pathway was dependent on several different G proteins. The massive release of arachidonic acid was likely due to stimulation of PLA2 (17).
Our experiments showed that the H1-receptorantagonist DPH could inhibit histamine-stimulated signaling leading to bronchial epithelial IL-8 expression. Increasing doses of DPH above 1 µM showed less suppression of histamine activation, consistent with DPH acting as a partial agonist at the H1 receptor (2, 12).
We observed a good correlation between the inhibitory effects of DPH, MK-886, and Zileuton upon histamine-stimulated IL-8 transcriptional activation, IL-8 mRNA levels, and IL-8 protein secretion. From this correlation, we conclude that the major level of regulation of IL-8 expression in bronchial epithelial cells occurs at the level of transcription, as has been described previously (25). It also justifies our use of the IL-8 luciferase reporter gene assay as a biologically relevant screening assay for evaluating immunomodulators of bronchial epithelial cell IL-8 expression.
The transcriptional induction of IL-8 in diverse cell types depends on
activation of NF-B, and IL-8 NF-
B activation can be augmented by
activation of NF-IL-6 and AP-1 (22). Our experiments revealed that
histamine could induce IL-8 NF-
B and AP-1 DNA-binding activities in
16HBE cells. The histamine-induced IL-8 NF-
B DNA-binding complex in
bronchial epithelial cells contained immunoreactive p65, in agreement
with the immunochemical identification of p65 in IL-8 NF-
B in
glioblastoma and gastric carcinoma cell lines (22). Although DPH
inhibited histamine induction of both IL-8 NF-
B and AP-1 DNA-binding
activities, MK-886 inhibited only NF-
B binding.
In our studies, MK-886 and Zileuton inhibited histamine-stimulated IL-8
transcription and IL-8 protein secretion. MK-886 inhibition of IL-8
NF-B and not of AP-1 DNA-binding activity correlated with the
inhibition of IL-8 transcription and IL-8 expression, underscoring the
essential requirement for activation of NF-
B for bronchial
epithelial cell IL-8 expression. The inhibitory effects of MK-886 and
Zileuton implicate 5-lipoxygenase signaling and lipid signaling
intermediates such as LTB4 in
histamine induction of IL-8 transcription. We demonstrated that 16HBE
cells produced LTB4 after
stimulation with histamine. Further support that 5-lipoxygenase signaling is involved in the histamine-induced activation of IL-8 NF-
B was provided with the alternative FLAP inhibitor L-655,238, which also caused inhibition of IL-8 transcriptional activation. Compellingly, the inhibition of histamine signaling with FLAP inhibitors and Zileuton could be rescued with exogenous
LTB4. Our conclusion is that
histamine stimulates 16HBE cell production of endogenous
LTB4, which acts downstream to
activate NF-
B and IL-8 transcription; FLAP inhibitors and Zileuton
diminish the production of endogenous
LTB4, decreasing IL-8
transcription, and exogenous LTB4
can restore downstream activation of NF-
B and IL-8.
Activation of 5-lipoxygenase can generate reactive oxygen intermediates
capable of activating NF-B (3, 6, 20). Los et al. (20) analyzed T
lymphocyte activation triggered through the CD28 receptor and showed a
role for 5-lipoxygenase and LTB4 in activation of NF-
B DNA-binding activity and expression of IL-2.
The FLAP inhibitor MK-886 potently inhibited NF-
B
DNA-binding activity and IL-2 secretion triggered by anti-CD28 and
anti-CD3 activation (20). MK-886 showed no inhibitory effects at the level of induced DNA binding of the transcription factors NF of activated T cells or AP-1 (20).
Recently, LTB4 has been identified as an activating ligand of the ryanodine-receptor intracellular calcium- release channel (32). Striggow and Ehrlich (32) showed that 100 nM LTB4 was sufficient for full activation of the ryanodine receptor purified from canine cerebellar microsomes and reconstituted into planar lipid bilayers. Interestingly, arachidonic acid, a precursor for synthesis of LTB4, was found to be an inhibitor of the inositol 1,4,5-trisphosphate (IP3)-gated intracellular calcium channel. The authors concluded that the differential effects of arachidonic acid and LTB4 on the IP3 receptor and ryanodine receptor would provide an additional level of complexity in calcium signaling in cells that contained both forms of intracellular calcium channels (32). In neutrophils loaded with the fluorescent calcium indicator quin 2, LTB4 caused a rapid rise in intracellular calcium due both to influx from the extracellular medium and to efflux from intracellular stores (18).
A cell-surface membrane receptor for LTB4 has recently been cloned from retinoic acid-differentiated HL-60 cells (35). The cDNA predicts a seven-span receptor with limited sequence similarities to the human IL-8 receptor and formyl-peptide receptor (35). Expression of the LTB4-receptor cDNA in heterologous cells showed that 100 nM LTB4 induced a rapid increase in intracellular calcium and IP3 accumulation (35). These increases were partially inhibited by pertussis toxin, implying that the LTB4 receptor couples to intracellular signaling pathways through pertussis-sensitive and -insensitive G proteins (35). Northern analysis of LTB4-receptor expression showed expression in leukocytes, spleen, and thymus, with no expression detected in lung tissues.
LTB4 has also recently been shown
to be a direct intracellular activating ligand for the nuclear
transcription factor peroxisome proliferator-activated receptor (PPAR;
see Ref. 9). LTB4 was shown to
specifically activate PPAR-driven transcription and also to bind
directly to a fusion protein consisting of bacterial glutatathione
S-transferase fused to the
ligand-binding domain of PPAR
.
The potent induction of cPLA2 mRNA
identifies cPLA2 as an additional
gene target of histamine induction. The induction of cPLA2 mRNA is likely followed by
translation into protein. However, we believe that increases in
cPLA2 protein will occur too late to contribute significantly to histamine-stimulated production of
LTB4 and NF-B and IL-8
transcriptional activation at 6 h. Nevertheless, upregulation of
cPLA2 by histamine likely
increases the later generation of arachidonic acid substrates for
5-lipoxygenase, as described by Leurs et al. (17) in H1
receptor-transfected Chinese hamster ovary cells. In this manner,
histamine stimulation could upregulate its own signaling pathway in a
positive feedback loop. This might be the basis for the increased
sensitivity to histamine (1 µM) described in epithelial cells derived
from airways of asthmatics but not from normal volunteers (5).
We propose that LTB4, produced
endogenously by bronchial epithelial cell 5-lipoxygenase or exogenously
from activated macrophages or neutrophils, activates bronchial cell
transcription factor NF-B and inflammatory cytokine gene expression.
This activation might involve transient increases in calcium mediated
through intracellular ryanodine receptors (32) or possibly through
plasma membrane, G protein-coupled
LTB4 receptors (35).
Alternatively, LTB4 might activate
NF-
B through mechanisms related to the direct intranuclear
activation of the PPAR
transcription factor (9).
Our findings that histamine acts through H1 receptors to stimulate bronchial epithelial cell synthesis of LTB4, which induces IL-8 expression, suggest that therapeutic strategies to decrease airway inflammation should include efforts directed at histamine-triggered and leukotriene-mediated intracellular inflammatory signaling pathways.
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ACKNOWLEDGEMENTS |
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We thank Glenn D. Rosen for helpful discussions and review of the manuscript.
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FOOTNOTES |
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This work was supported by grants from the California Affiliate of the American Lung Association, the Donald E. and Delia B. Baxter Foundation, and National Institute of Allergy and Infectious Diseases Grants K04-AI-01147 and R01-AI-39624 to P. N. Kao. Y. Aoki received salary support from Saga Medical School, Saga, Japan.
Address for reprint requests: P. N. Kao, Pulmonary and Critical Care Medicine, Stanford Univ. Medical Center, Stanford, CA 94305-5236.
Received 10 October 1997; accepted in final form 6 March 1998.
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