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Centre d’Immunologie Pierre Fabre, Saint Julien en Genevois, France;
Institut National de la Santé et de la Recherche Médicale, Unité 416, Institut Pasteur, Lille, France;
Pharmacie Centrale, Centre Hospitalier, Hazebrouck, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, a potent DC1-driving
factor. All these effects are mediated through both H1 and H2
receptors. These data show that histamine is a potent DC2-polarizing
factor and provide evidence for a novel mechanism that explains the
initiation and maintenance of a predominant Th2 response in allergic
disorders. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In allergic individuals a contact with the sensitizing allergen results
in IgE-dependent activation of mast cells that subsequently release
preformed (e.g., histamine and TNF-
) and newly synthesized mediators
(e.g., PGE2) involved in the pathologic processes
associated with allergic reaction (5). Among them,
histamine participates in vasodilatation, smooth muscle contraction,
mucus hypersecretion, and edema formation (6, 7).
Histamine also presents immunoregulatory properties as it modulates
cytokine production by different cell types (6, 8, 9, 10, 11, 12, 13).
Histamine exerts its effects through three receptors, H1, H2 (both
expressed on lymphoid and nonlymphoid cells), and H3 (mainly expressed
in the brain) (6, 7, 8, 9, 11, 12). Recently, a new receptor for
histamine, H4, has been identified (14).
Dendritic cells (DC)2
are the most potent APC. In peripheral tissues, immature DC capture Ags
(15, 16) and, upon contact with stress factors (such as
TNF- or LPS), undergo a maturation process; they increase
costimulatory and accessory molecule expression, produce cytokines,
lose their capacity to process Ags, neoexpress CD83 (for human cells),
and migrate to the lymphoid organs where they prime naive Ag-specific T
cells (15, 16). Based on their ability to favor Th1 vs Th2
differentiation, mature DC have been called DC1 or DC2, respectively
(3). Myeloid DC give rise to DC1 or DC2, depending on the
nature of the maturation stimuli influencing IL-12 production (a potent
Th1-driving cytokine) (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27). In addition to many viral
and bacterial products (e.g., LPS, Staphylococcus aureus
Cowan strain I, bacterial DNA, and dsRNA) that can induce or enhance
IL-12 production by human myeloid DC (17, 18, 19, 20, 21), IFN-
seems to be the most potent DC1-promoting factor (19, 22).
In contrast, PGE2 (23, 24), cholera
toxin (25), and ATP (26) contribute to the
development of human DC2. A filarial nematode-secreted product, ES-62,
also promotes the differentiation of murine DC toward a DC2 phenotype
(27).
To date, the nature of mediator(s) present selectively in allergic disorders and involved in DC2 polarization remains to be determined. As histamine has been reported to inhibit IL-12 production by human monocytes (11) and to activate human immature DC (28), we therefore tested whether it may affect maturing DC polarization. We report that histamine is a potent DC2-polarizing mediator.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PBMC were isolated from healthy volunteers by standard density
gradient centrifugation on Ficoll-Paque (Amersham Pharmacia Biotech,
Uppsala, Sweden). Monocytes were purified from PBMC by positive
selection using a magnetic cell separator (MACS, Miltenyi Biotec,
Bergisch Gladbach, Germany) according to the manufacturer’s
instructions. Purity assessed by FACS analysis using an FITC-labeled
anti-CD13 mAb (Cymbus, Chandlers Ford, U.K.) was >98%. Monocytes
were cultured in complete medium (CM) consisting of RPMI 1640 medium
supplemented with 10% FCS, 2 mM L-glutamine, 50 U/ml
penicillin, 50 µg/ml streptomycin, 10 mM HEPES, and 0.1 mM
nonessential amino acids (all from Life Technologies, Cergy Pontoise,
France) at 5 x 106 cells/5 ml/well in
six-well tissue culture plates (Costar, Cambridge, MA) with 20 ng/ml
IL-4 and 20 ng/ml GM-CSF (both from R&D Systems, Abingdon, U.K.). On
day 7, cells were analyzed by FACS as described above; only homogeneous
immature DC populations characterized by high levels of CD1a (mean
fluorescence intensity, 100–800) and no CD83 expression were used. DC
were then recultured at 105 cells/200 µl/well
in 96-well flat-bottom tissue culture plates (Costar) in
cytokine-containing CM without or with different concentrations of
histamine (Sigma, St. Louis, MO). In some experiments DC were also
exposed to 5 x 10-5 M of the H1, H2, or H3
receptor antagonists, mepyramine, cimetidine, or thioperamide (all from
Sigma), respectively, 1 h before addition of histamine or were
exposed to 10-5 M of the H1 and H2 receptor
agonists, histamine-trifluoromethyl-toluidide dimaleate and amthamine
dihydrobromide, respectively (both from Biomol, Plymouth Meeting, PA).
In others, immature DC were stimulated with LPS (from Escherichia
coli isotype 0111:B4, Sigma) alone or in combination with IFN-
(R&D Systems) and/or histamine. When indicated, mature DC were
harvested, washed, recultured at 105 cells/200
µl/well in CM without cytokines, and stimulated with 1 µg/ml
soluble recombinant CD40 ligand (CD40L; Apotech Biochemicals,
Epalinges, Switzerland).
Flow cytometric measurement of CD86 expression
Immature DC exposed to combinations of increasing doses of histamine and/or LPS for 48 h were stained with a FITC-labeled anti-CD86 (PharMingen, San Diego, CA). Control isotype was purchased from Becton Dickinson. FACS analysis was performed using a FACScan cytofluorometer (BD Biosciences, Franklin Lakes, NJ). Results are expressed as a percentage of positive cells.
Mixed lymphocyte reaction
Day 7 DC were washed and recultured at 2.5 x 106 cells/5 ml/well in six-well culture plates in cytokine-containing CM, then were or were not stimulated with 10-5 M histamine and different concentrations of LPS. After 24 h, DC were irradiated (3000 rad) and cultured with T cells in quintuplicate. DC at 103 cells/200 µl/well in 96-well flat-bottom plates were cultured with 105 allogenic T cells purified from PBMC from healthy volunteers by rosetting with SRBC (the purity was assessed by FACS analysis using a FITC-labeled anti-CD3 mAb was >95%). After 5 days, cells were pulsed during the last 16 h with [3H]thymidine (0.25 µCi/well; Amersham Pharmacia Biotech). Radioactive incorporation was measured by standard liquid scintillation counting, and results are expressed as counts per minute (mean ± SD of quintuplicate values).
IL-8 and IL-12 quantification
The concentrations of IL-8 and IL-12 were determined in the 24- or 48-h cell-free culture supernatants by ELISA (R&D Systems; sensitivity, 10 and 0.5 pg/ml, respectively). Results are expressed as nanograms per milliliter or picograms per milliliter and are the mean ± SD (n = 4).
Analysis of mRNA expression by RT-PCR
The expression of the mRNA encoding for human histamine H1, H2, and H3 receptors was determined by RT-PCR. Total RNA from immature DC was extracted using TRIzol reagent (Life Technologies), and the single-strand cDNA was synthesized using 2 µg total RNA by RT using an oligo(dT) primer (Amersham Pharmacia Biotech). PCR reactions were performed with cDNA corresponding to 50 ng total RNA and primers designed to amplify the coding sequence of the histamine receptors (29). The PCR reaction was as follows: 94°C for 5 min; 30 cycles of 94°C for 30 s, 60°C for 30 s, and 72°C for 1 min; followed by a final extension at 72°C for 5 min. RNA integrity and cDNA synthesis was verified by amplifying GAPDH cDNA. The amplified fragments were size-separated on a 1% agarose gel and visualized by ethidium bromide.
Induction of memory-type lymphokines in maturing Th cells and intracellular staining
After rosetting and CD8 depletion, CD4+
CD45RA+ naive T cells were purified by MACS
(Miltenyi Biotec) using a positive selection of
CD45RA+ cells. Purified naive Th cells (5 x
104) were cocultured with irradiated allogenic DC
(2 x 104) matured in presence of 10 ng/ml
LPS, 10 ng/ml LPS plus 100 ng/ml IFN-, 10 ng/ml LPS plus
10-5 M histamine, and 10 ng/ml LPS plus 100
ng/ml IFN- plus 10-5 M histamine. On day 5,
50 U/ml rhIL-2 (R&D Systems) was added, and the cultures were expanded
for the next 7 days. On day 12, the quiescent Th cells were washed and
restimulated with 10 ng/ml PMA (Sigma) plus 1 µg/ml ionomycin
(Calbiochem, San Diego, CA) for 5 h. Brefeldin A (Sigma, 10
µg/ml) was added during the last 2 h of culture. Cells were
fixed, permeabilized, stained with FITC-labeled anti-IFN- mAb
(PharMingen) and PE-labeled anti-IL-4 mAb (BD Biosciences), and
analyzed on a FACScan cytofluorometer (BD Biosciences).
Statistical analysis
Statistical analysis were performed using Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-12 is a potent Th1-inducing factor. We previously observed that histamine transiently activates immature DC, but does not induce IL-12 production or DC maturation (28). In inflammatory sites, histamine may act in concert with DC maturation factors such as LPS (15, 16). We therefore tested the combined effects of histamine and LPS on IL-12 production by immature DC.
As expected, LPS (0.1–10 ng/ml) induced IL-12 production by DC (Fig. 1
A). At any concentration of
LPS tested, histamine dose-dependently decreased LPS-induced IL-12
production, with an effect significant at 10-7 M
and maximum at 10-5 M, the highest concentration
tested (Fig. 1A).
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B). While
10-5 M histamine inhibited 10 ng/ml LPS-induced
IL-12 production (decrease of 87 ± 10% (mean ± SD);
n = 4), this inhibition was reduced to 35 ± 7 and
20 ± 5% by H1 and H2 receptor antagonists, respectively (Fig. 1B). In our experimental conditions no RT-PCR product for H3
receptor was detected in immature DC and 5 x
10-5 M H3 antagonist thioperamide, which also
inhibited histamine binding on H4 receptor (14), had no
effect on IL-12 production by LPS- plus histamine-treated DC (Fig. 1B). We therefore analyzed whether this down-regulation of
IL-12 production induced by histamine is associated with a global
inhibitory effect of histamine on LPS-induced DC maturation.
LPS and histamine are known to induce numerous cytokine production by
immature DC (i.e., IL-6 and IL-8) (28). We observed that
histamine synergized with LPS in inducing IL-8 (Fig. 1C) and
IL-6 production (data not shown) by immature DC. Histamine up-regulated
costimulatory molecule expression (i.e., CD86, CD54, and MHC class II
molecules) and DC costimulatory properties (28). Histamine
up-regulated CD86 (Fig. 1D), CD54, CD83, MHC class II
expression (data not shown), and DC costimulatory properties (Fig. 1E) induced by suboptimal concentrations of LPS. Thus, these
data show that histamine acts together with LPS to induce DC maturation
while inhibiting LPS-induced IL-12 production by DC.
Histamine decreases the ability of maturing myeloid DC to produce IL-12 upon stimulation
Immature DC treated for 2 days with 10 ng/ml LPS acquired a phenotype of fully mature CD83+ DC (15, 16), and addition of histamine during maturation did not affect cell surface molecule expression (i.e., CD54, CD86, CD83, and MHC class I and II molecules) or DC costimulatory properties (data not shown).
IL-12 produced by mature DC at the time of T cell priming controls Th cell polarization (3). As histamine prevents LPS-induced IL-12 production by immature DC, we therefore tested whether the presence of histamine during DC maturation may modulate the ability of mature DC to produce IL-12 upon stimulation with soluble CD40L (to mimic signal provided by T cells).
DC maturation was induced by LPS in the presence of IFN-
(22) and/or histamine. After 2 days, mature DC were
stimulated with soluble CD40L (Fig. 2).
In the absence of CD40L stimulation, no IL-12 production was detected
in any population of mature DC (data not shown). LPS-matured DC
stimulated with CD40L produced low levels of IL-12 (Fig. 2A). As expected (22), addition of IFN-
during LPS-induced maturation instructed maturing myeloid DC to produce
high levels of IL-12 upon stimulation (Fig. 2A). Histamine
down-regulated the capacity of LPS-matured DC to produce IL-12.
Moreover, at any concentration of INF tested (0.25–100 ng/ml),
histamine greatly impaired the ability of IFN--treated DC to produce
IL-12 in response to CD40L (Fig. 2A). This inhibitory effect
of histamine was dose dependent, significant at
10-7 M, maximum at 10-5 M
(the highest concentration tested; Fig. 2A), and mediated
through both H1 and H2 receptors (Fig. 2B). Treatment with
10-5 M histamine inhibited 84 ± 9%
(mean ± SD; n = 4) of 10 ng/ml LPS- plus 100
ng/ml IFN--induced IL-12 production. In the presence of H1 and H2
receptor antagonists, this inhibition was partly prevented (inhibition
of 40 ± 5 and 14 ± 4%, respectively), while no significant
effect of the H3 receptor antagonist was observed (Fig. 2B).
As expected, H2 and, to a lesser extent, H1 receptor agonists also
decreased IL-12 production by mature DC (decreases of 68 ± 8%
and 35 ± 5%, respectively).
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plus IL-1
plus IFN- also
leads to mature DC that produce high levels of IL-12 upon stimulation
(23). In this condition of maturation, addition of
histamine impairs their ability to produce IL-12 (decrease of 83
± 7.5% with 10-5 M histamine upon stimulation
with CD40L; data not shown).
In conclusion, histamine and IFN- reciprocally regulate the capacity
of maturing DC to secrete IL-12. The presence of histamine during DC
maturation dose-dependently suppresses their ability to produce IL-12
upon stimulation.
Histamine polarizes uncommitted maturing DC toward DC2 and inhibits
IFN--induced DC1
Priming of naive T cells with IL-12-deficient DC leads to the
generation of Th2-polarized cells (23). We therefore
tested whether the presence of histamine during DC maturation may
affect naive Th cell polarization. Mature DC, obtained by treating
immature DC for 2 days with LPS in the absence or the presence of
IFN- and/or histamine, were cultured with naive allogenic
CD4+ CD45RA+ T cells. We
then analyzed the pattern of IL-4 and IFN- production by T cells
after stimulation. In all conditions mature DC induced similar naive T
cell proliferative responses (data not shown). Naive T cells primed
with LPS-treated DC led to a low percentage of IFN-- and
IL-4-producing cells (31 ± 8% and 7 ± 3%, respectively
(mean ± SD); n = 3; Fig. 3) (22). Addition of
histamine during LPS-induced DC maturation promoted a Th2 pattern, as
assessed by an up-regulation of the percentage of IL-4-producing cells
(3.2 ± 0.4-fold) and a down-regulation of the percentage of
IFN--producing cells (1.6 ± 0.2-fold; Fig. 3). As expected
(22), T cells primed by LPS- plus IFN--treated DC
differentiated into Th1 cells characterized by a high percentage of
IFN--producing cells (68 ± 20%) and few IL-4-producing cells
(2 ± 0.5%). In this condition of maturation, addition of
histamine increased the percentage of IL-4-producing cells (5 ±
0.3-fold) and down-regulated the percentage of IFN--producing cells
(4.6 ± 0.8-fold), thereby preventing the development of a Th1-biased
response and inducing a polarized Th2 response (Fig. 3). Thus,
histamine-treated maturing DC drive T cell polarization toward a Th2
phenotype even in presence of IFN-, a strong Th1-polarizing
stimulus.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, a potent DC1-polarizing cytokine
(19, 22).
Histamine transiently activates human immature DC in vitro
(28). In vivo, bacterial components (such as LPS) and
mediators released by activated mast cells (i.e., IL-1 and preformed
TNF-) may act in concert with histamine on peripheral DC
(5). When present during the maturation process together
with concentrations of maturation factors leading to fully mature DC
(such as LPS or TNF- plus IL-1), histamine does not affect DC
costimulatory properties, but polarizes them into DC2. These effects of
histamine were significant at concentrations as low as
10-7 M. This concentration is comparable to
those measured in nasal lavages from allergic subjects after allergen
challenge and in tissues after mast cell degranulation (30, 31).
To date, IFN- is the most potent DC1-promoting factor described
(19, 22). PBMC and T cells from allergic patients
stimulated with the sensitizing allergen produce levels of IFN- that
are similar to or even higher than those in healthy subjects
(32). Furthermore, histamine by itself has been shown to
induce IFN- and IL-18 production by PBMC (13).
Interestingly, we report that histamine polarizes DC into DC2 even in
presence of a high concentration of IFN- (i.e., 100 ng/ml). The dual
effects of histamine and IFN- on DC polarization may contribute to
explain why, in allergic subjects, a predominant Th2-biased profile
persists together with IFN- production in response to allergen.
The actual concept is that DC1/DC2 polarization is mainly associated
with their ability to produce high or low levels of IL-12, respectively
(17, 18, 19, 20, 21, 22, 23, 24, 25, 26). In agreement with this observation, histamine
dramatically decreases the IL-12 production induced by LPS plus
IFN-. Surprisingly, DC treated with histamine, IFN-, and LPS or
with LPS alone produce similar levels of IL-12, whereas only
histamine-, IFN--, and LPS-treated DC trigger a Th2 polarization.
This suggests that in addition to IL-12 production, other signals, such
as soluble factors or contact-dependent mechanisms, may control Th cell
polarization by DC (3).
Using specific receptor agonists and antagonists, we show that histamine inhibits IL-12 production and favors DC2 polarization by acting through both H1 and H2 receptors. The involvement of the H2 receptor is in agreement with the observation that histamine decreases IL-12 production by PBMC through the H2 receptor (11, 12). These observations point out a potential beneficial role for anti-H2 molecules, together with the anti-H1 molecules currently used, in the treatment of allergic disorders.
Signaling through the H2 receptor involves cAMP generation (7). The DC2-polarizing molecules, PGE2 and cholera toxin, have been shown to favor DC2 polarization by increasing intracellular cAMP (33). Together, these data suggest that high levels of intracellular cAMP may favor DC2 polarization (23). As PGE2 is produced by activated monocytes and mast cells, it is tempting to speculate that upon mast cell degranulation histamine and PGE2 may act in concert to favor Th2 polarization in allergic disorders.
In addition, we report that H1 receptor is involved in histamine-induced DC2. Signaling via the H1 receptor involves the activation of phospholipase C and is cAMP independent (6). Finally, it has been reported that the effect of ATP on DC2 generation was not mediated through cAMP (26). Taken together, these data suggest the existence of both cAMP-dependent and cAMP-independent pathways in DC2 differentiation.
In conclusion, we show here that histamine, a preformed mediator released by mast cells from allergic subjects upon contact with the sensitizing allergen, polarizes maturing DC into DC2 through both H1 and H2 receptors. This demonstrates a new mechanism that contributes to the initiation and maintenance of allergen-specific, Th2-biased responses in allergic disorders. By polarizing DC2, histamine may also favor the induction of Th2-biased responses and sensitization to diverse encountered allergens, as observed in atopics.
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Footnotes |
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2 Abbreviations used in this paper: DC, dendritic cells; CD40L, CD40 ligand; CM, complete medium.
Received for publication May 29, 2001. Accepted for publication July 19, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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via histamine H2 receptors. J. Exp. Med. 174:281. in human peripheral blood mononuclear cells. J. Immunol. 164:6640.This article has been cited by other articles:
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H. Hashizume, T. Horibe, H. Yagi, N. Seo, and M. Takigawa Compartmental Imbalance and Aberrant Immune Function of Blood CD123+ (Plasmacytoid) and CD11c+ (Myeloid) Dendritic Cells in Atopic Dermatitis J. Immunol., February 15, 2005; 174(4): 2396 - 2403. [Abstract] [Full Text] [PDF]
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S.-W. Qiao, J. Piper, G. Haraldsen, I. Oynebraten, B. Fleckenstein, O. Molberg, C. Khosla, and L. M. Sollid Tissue Transglutaminase-Mediated Formation and Cleavage of Histamine-Gliadin Complexes: Biological Effects and Implications for Celiac Disease J. Immunol., February 1, 2005; 174(3): 1657 - 1663. [Abstract] [Full Text] [PDF]
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D. M. Jawdat, E. J. Albert, G. Rowden, I. D. Haidl, and J. S. Marshall IgE-Mediated Mast Cell Activation Induces Langerhans Cell Migration In Vivo J. Immunol., October 15, 2004; 173(8): 5275 - 5282. [Abstract] [Full Text] [PDF]
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I. Couillin, I. Maillet, B. B. Vargaftig, M. Jacobs, G. C. Paesen, P. A. Nuttall, J. Lefort, R. Moser, W. Weston-Davies, and B. Ryffel Arthropod-Derived Histamine-Binding Protein Prevents Murine Allergic Asthma J. Immunol., September 1, |
) or the
presence (
) of 10-5 M histamine. IL-8 production was
determined by ELISA, and results are expressed as nanograms per
milliliter and are the mean ± SD of three separate experiments.
D, Immature DC were exposed to combinations of
increasing doses of histamine and/or LPS, and CD86 expression was
analyzed by FACS after 48 h. Results are expressed as a percentage
of positive cells and are representative of three experiments.
E, Immature DC were either untreated or exposed for
48 h to different doses of LPS in the absence (
