Histamine Is a Potent Inducer of IL-18 and IFN- Γ in Human Peripheral Blood Mononuclear Cells

Histamine Is a Potent Inducer of IL-18 and IFN- γ in Human Peripheral Blood Mononuclear Cells

This information is current as Hideo Kohka, Masahiro Nishibori, Hiromi Iwagaki, Naoki of September 25, 2021. Nakaya, Tadashi Yoshino, Kenta Kobashi, Kiyomi Saeki, Noriaki Tanaka and Tadaatsu Akagi J Immunol 2000; 164:6640-6646; ; doi: 10.4049/jimmunol.164.12.6640

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Histamine Is a Potent Inducer of IL-18 and IFN-␥ in Human Peripheral Blood Mononuclear Cells

Hideo Kohka,*‡ Masahiro Nishibori,1† Hiromi Iwagaki,* Naoki Nakaya,† Tadashi Yoshino,‡ Kenta Kobashi,* Kiyomi Saeki,† Noriaki Tanaka,* and Tadaatsu Akagi‡

-Histamine (10؊7 to 10؊4 M) concentration-dependently stimulated the production of IL-18 and IFN-␥ and inhibited the produc tion of IL-2 and IL-10 in human PBMCs. Histamine in the same concentration range did not induce the production of IL-12 at all. The stimulatory or inhibitory effects of histamine on cytokine production were all antagonized by H2 receptor antagonists ranitidine and famotidine in a concentration-dependent manner, but not by H1 and H3 receptor antagonists. Selective H2 receptor agonists, 4-methylhistamine and dimaprit, mimicked the effects of histamine on ﬁve kinds of cytokine production. The EC50 values of histamine, 4-methylhistamine, and dimaprit for the production of IL-18 were 1.5, 1.0, and 3.8 ␮M, respectively. These ﬁndings Downloaded from indicated that histamine caused cytokine responses through the stimulation of H2 receptors. All effects of histamine on cytokine responses were also abolished by the presence of either anti-IL-18 Ab or IL-1␤-converting enzyme/caspase-1 inhibitor, indicating that the histamine action is dependent on mature IL-18 secretion and that IL-18 production is located upstream of the cytokine cascade activated by histamine. The addition of recombinant human IL-18 to the culture concentration-dependently stimulated IL-12 and IFN-␥ production and inhibited the IL-2 and IL-10 production. IFN-␥ production induced by IL-18 was inhibited by anti-IL-12 Ab, showing the marked contrast of the effect of histamine. Thus histamine is a very important modulator of Th1 cytokine production in PBMCs and is quite unique in triggering IL-18-initiating cytokine cascade without inducing IL-12 http://www.jimmunol.org/ production. The Journal of Immunology, 2000, 164: 6640–6646.

nterleukin-18 was originally characterized as an IFN-␥-in- infection (16, 17), autoimmune diabetes (18), P. acnes-primed ducing factor in the blood of mice primed with Propionibac- LPS-induced hepatitis (19), and autoimmune encephalomyelitis I terium acnes and stimulated with LPS (1). IL-18 is secreted (20). The enhancement of antitumor immunity by IL-18 alone or in from LPS-activated monocytes/macrophages but also from a wide combination with IL-12 has also been described recently (21–23). variety of cells (2–5). IL-18 is synthesized as a precursor protein Thus, IL-18 plays an important role in host immune and autoim- ␤ mune responses. that requires cleavage with the IL-1 -converting enzyme/ by guest on September 25, 2021 caspase-1 for activity as in the case of IL-1␤ (6, 7). After cleavage, Histamine is a well-known mediator of inﬂammation and aller- the bioactive mature IL-18 is secreted from the cells. In addition to gic response. In addition to the stable pool of histamine in mast the homology of the primary amino acid sequences (1), IL-18 and cells and basophilic leukocytes, the presence of histamine with a IL-1␤ share a common secondary and tertiary structure, a different dynamic property, called inducible or nascent histamine, ␤-pleated sheet structure. Thus, IL-18 belongs to the IL-1 family. was suggested in the earlier works (24, 25). Later, many groups Moreover, it has been shown that they also have similar entity of reported the induction of histidine decarboxylase, a histamine-syn- receptor complex, ␣ binding, and ␤ signaling peptide chains (8, 9). thesizing enzyme, by LPS, cytokines, and lymphocyte mitogen in IL-18 is functionally similar to IL-12 in mediating Th1 response macrophages (26), T lymphocytes (27), and in many peripheral and NK cell activity. IL-18 with IL-12 synergistically produced tissues (28, 29). The synthesized histamine appeared not to enter IFN-␥ in T lymphocytes and monocytic cells (10–14) in which the storage pool inside the cells, but rather was spontaneously re- IL-12 has been shown to up-regulate IL-18 receptor (12). Kohka et leased from the cells (30). The induction of histidine decarboxyl- al. (15) demonstrated that IL-18 up-regulated the ICAM-1 expres- ase and this kinetic property of histamine may endow histamine with a mobile nature under the diverse cytokine environment. Al- sion in a KG-1 monocytic cell line through the IFN-␥-independent though it has long been suggested that histamine may be one of the pathway. regulators of immune response (31–34), the estimated functional IL-18 has been suggested to be involved in many pathological roles of histamine as immunomodulator were often controversial conditions including the host defense against fungal and bacterial probably due to the differences in the cell preparations used and the complexity of the involvement of histamine in immunomodu- lation (35).

† ‡ In the present study, we investigated the effects of histamine on Departments of *Surgery, Pharmacology, and Pathology, Okayama University ␥ Medical School, Okayama, Japan the production of IL-18, IL-12, IFN- , IL-10, and IL-2 in human Received for publication December 9, 1999. Accepted for publication March PBMCs in vitro. We found that histamine was a strong inducer of 23, 2000. IL-18 production through the stimulation of H2 receptors in The costs of publication of this article were defrayed in part by the payment of page PBMCs and that histamine in turn regulated IL-18-triggered charges. This article must therefore be hereby marked advertisement in accordance activation of cytokine cascade without inducing IL-12 produc- with 18 U.S.C. Section 1734 solely to indicate this fact. tion. Therefore, it was concluded that histamine is an important 1 Address correspondence and reprint requests to Dr. Masahiro Nishibori, Department of Pharmacology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama immunomodulator, in addition to being an inﬂammatory 700-8558, Japan. E-mail address: [email protected] mediator.

FIGURE 1. Effect of IL-18 on IL- 12, IL-2, IFN-␥, and IL-10 production in PBMCs. PBMCs (5 ϫ 105/ml) were cultured in the presence of increasing concentrations of IL-18 for 24 h. At the end of the culture, the concentrations of IL- 12, IL-2, IFN-␥, and IL-10 in the conditioned media were determined Downloaded from p Ͻ 0.01 as ,ءء ;p Ͻ 0.05 ,ء .using an ELISA kit as described in Materials and Methods. The results are the means Ϯ SEM of three different donors compared with the value in the absence of IL-18.

Materials and Methods coated with mAb specific for the CD19 (Pan-B cells) surface Ag. Total PBMCs at 1 ϫ 106 cells/ml were incubated and gently mixed with the Reagents and drugs magnetic beads at 4°C for 30 min. Bead-cell complexes were eliminated by http://www.jimmunol.org/ Recombinant human IL-18, anti-IL-18 mAb, and caspase-1 inhibitor Z-tyr- magnetic separation. The T/monocyte cell-enriched preparations contained Val-Ala-Asp-fluoromethyl ketone (YVAD-FMK) were purchased from 75%/80% T/monocyte cells, and B cell-enriched preparations contained Medical & Biological Laboratories (Nagoya, Japan). Anti-IL-12 mAb was 70% B cells as determined by flow cytometry (FACScan, Cell Quest, Bec- purchased from PharMingen (San Diego, CA). Histamine was purchased ton Dickinson, Mountain View, CA) with FITC-conjugated anti-CD3 Ab, from Nakalai Tesque (Kyoto, Japan). Dimaprit and 4-methylhistamine anti-CD14 Ab, and anti-CD19 Ab. were kindly donated from Drs. W. A. M. Duncan and D. J. Durant (The Research Institute, Smith Kline and French Laboratories, Welwyn Garden City, Herts, U.K.). d-Chlorpheniramine maleate, ranitidine, and famotidine Determination of histamine and tele-methylhistamine were provided by Yoshitomi Pharmaceutical (Tokyo, Japan), Glaxo Japan (Tokyo, Japan), and Yamanouchi Pharmaceutical (Tokyo, Japan), respec- The histamine and tele-methylhistamine levels in the cell-free supernatant by guest on September 25, 2021 tively. Thioperamide hydrochloride was provided by Eisai (Tokyo, Japan). of conditioned media after the incubation with IL-18 (0.1–10 ng/ml) for 2, 12, and 24 h were determined as described previously (36). Isolation and culture of PBMCs Normal human PBMCs were obtained from human volunteers after oral Statistical examination informed consent. Twenty to 50 ml of peripheral blood was withdrawn Statistical significance was evaluated using ANOVA followed by the Stu- from the vein of the forearm. PBMCs were isolated from the buffy coat of dent’s two-tailed t test. Values of p Ͻ 0.05 were considered to be statis- 10 healthy volunteers by centrifugation on a density gradient of Ficoll- tically significant. Paque (Pharmacia, Uppsala, Sweden), then washed three times in RPMI 1640 medium (Nissui, Tokyo, Japan) supplemented with 10% (v/v) heat- inactivated FCS, 20 ␮g/ml of kanamycin, and 100 ␮g/ml of streptomycin Results and penicillin (Sigma, St. Louis, MO). PBMCs were suspended at a final Effect of IL-18 on IL-12, IL-2, IFN-␥, and IL-10 production in concentration of 5 ϫ 105 cells/ml in RPMI 1640 medium supplemented with 10% (v/v) heat-inactivated FCS. PBMCs IL-18 (0.1–100 ng/ml) concentration-dependently stimulated the Cytokine assays release of IL-12 and IFN-␥ from human PBMCs when these cy- ϫ 5 tokines were determined 24 h after the start of culture with IL-18 PBMCs (5 10 cells/ml) were incubated with IL-18, histamine, H2 receptor agonist, and/or H1,H2,H3 receptor antagonists for 24 h at 37°C in (Fig. 1). In contrast, the productions of IL-2 and IL-10 during the a humidified atmosphere of 5% CO2 in air. All reagents were added to the same culture period were inhibited by IL-18 in a concentration- media at the start of incubation. After culture, the cell suspensions were dependent manner (Fig. 1). The effects of IL-18 on the production transferred into Eppendorf tubes and centrifuged. The cell-free supernatant of IFN-␥ and IL-10 were especially marked for IL-18 concentra- fractions were assayed for IL-18, IL-12, IL-2, IFN-␥, and IL-10 protein. The cytokines were measured using ELISAs employing the multiple Abs tions of 1 ng/ml and above. sandwich principle (for IL-18, MBL; for other cytokines, Quantikine, R&D Systems, Minneapolis, MN). The detection limits of the ELISAs for IL-18, IL-12, IL-2, IFN-␥, and IL-10 were 10 pg/ml. When the effect of anti-IL-18 Effect of histamine on IL-18, IL-12, IL-2, IFN-␥, and IL-10 mAb, anti-IL-12 mAb, or caspase-1 inhibitor was examined, these were production in PBMCs added to the culture media at the start of incubation with IL-18 (10 ng/ml) or histamine (100 ␮M). All experiments were done at least in triplicate Histamine alone concentration-dependently stimulated the release samples. of IL-18 from PBMC when IL-18 was determined 24 h after the

start of culture with histamine (Fig. 2). The EC50 value for the Preparation of T cell/monocyte-rich, and B cell-rich fractions histamine effect on IL-18 production was estimated to be 1.5 ␮M. To obtain T cell/monocyte-enriched preparations, total PBMCs were de- Histamine in the same concentration range stimulated IFN-␥ pleted of B lymphocytes using magnetic beads (Dynal, Lake Success, NY) production, whereas IL-2 and IL-10 production was inversely 6642 HISTAMINE IS A POTENT INDUCER OF IL-18

FIGURE 2. Effect of histamine on IL-18, IL- 12, IL-2, IFN-␥, and IL-10 production in PBMCs. PBMCs (5 ϫ 105/ml) were cultured in the presence of increasing concentrations of histamine for 24 h. At the end of the culture, the concentrations of IL-18, IL- 12, IL-2, IFN-␥, and IL-10 in the conditioned media were determined using an ELISA kit as described in Materials and Methods. The IL-12 levels were below the detection limit (10 pg/ml). The results .p Ͻ 0.01 as compared with the value in the absence of histamine ,ءء ;p Ͻ 0.05 ,ء .are the means Ϯ SEM of three different donors Downloaded from

inhibited by histamine (Fig. 2). The levels of IL-12 were below the peramide did not exert any antagonizing action on the histamine

detection limit (10 pg/ml) for all of the histamine concentrations effect. Another H2 receptor antagonist, ranitidine, showed substan- examined (Fig. 2). tially similar effects to famotidine (data not shown).

Effects of histamine antagonists on the modulatory effects of http://www.jimmunol.org/

histamine on cytokine production in PBMCs Effects of selective H2 receptor agonists on IL-18, IL-12, IL-2, ␥ To examine the involvement of subtypes of histamine receptors in IFN- , and IL-10 in PBMCs

the effects of histamine, d-chlorpheniramine (H1 receptor antago- Selective H2 receptor agonists, dimaprit (37) and 4-methylhista-

nist), famotidine (H2 receptor antagonist), or thioperamide (H3 re- mine (38), concentration-dependently caused responses of IL-18, ceptor antagonist) was added to the culture medium at the con- IFN-␥, IL-2, and IL-10 identical with those of histamine (Fig. 4). ␮ ␮ ␮ centration of 1 or 100 M with histamine (100 M). These The EC50 values for the production of IL-18 were 3.8 M for antagonists alone did not affect on the basal levels of cytokine dimaprit and 1.0 ␮M for 4-methylhistamine, respectively. The ef-

production examined, except for the slight increase in IFN-␥ by fective antagonist proﬁle against histamine action, mimicry of his- by guest on September 25, 2021 ␮ ␮ 100 M famotidine. Famotidine at 1 and 100 M concentration- tamine actions by two selective H2 receptor agonists, and the rel- dependently antagonized the stimulatory or inhibitory effects of ative potencies of the three agonists as a whole indicated that the histamine on IL-18, IL-2, IFN-␥, and IL-10 production (Fig. 3). In effects of histamine on IL-18, IL-2, IFN-␥, and IL-10 were all

contrast, the same concentrations of d-chlorpheniramine and thio- mediated by the stimulation of H2 receptors.

FIGURE 3. Effects of histamine receptor antagonists on modulatory effects of histamine on cytokine production in PBMCs. PBMCs (5 ϫ 105/ml) were ␮ cultured with 100 M histamine in RPMI 1641 in the presence of d-chlorpheniramine (H1 antagonist), famotidine (H2 antagonist), or thioperamide (H3 antagonist) for 24 h. At the end of the culture, the concentrations of IL-18, IL-2, IFN-␥, and IL-10 in the conditioned media were determined using an p Ͻ 0.01 as compared with ,ءء ;p Ͻ 0.05 ,ء .ELISA kit as described in Materials and Methods. The results are the means Ϯ SEM of three different donors the value in the presence of histamine alone. The Journal of Immunology 6643 Downloaded from http://www.jimmunol.org/

FIGURE 4. Effect of dimaprit and 4-methylhistamine on IL-18, IL- 12, IL-2, IFN-␥, and IL-10 production in PBMCs. PBMCs (5 ϫ 105/ml) were cultured in RPMI 1641 in the presence of increasing concentrations of dimaprit or 4-methylhistamine for 24 h. At the end of the culture, the concentrations of IL-18, IL- 12, IL-2, IFN-␥, and IL-10 in the conditioned media were determined using an ELISA kit as described in Materials and Methods. The IL-12 p Ͻ 0.01 as ,ءء ;p Ͻ 0.05 ,ء .levels in all samples were below the detection limit (10 pg/ml). The results are the means Ϯ SEM of three different donors compared with the value in the absence of agonist. by guest on September 25, 2021

Effect of anti-IL-18 mAb, caspase-1 inhibitor, and anti-IL-12 the case of the addition of anti-IL-18 mAb. The complete mAb on cytokine responses to IL-18 and histamine in PBMCs inhibition of histamine effects by either anti-IL-18 Ab or The addition of anti-IL-18 mAb (10 ng/ml) to the culture caspase-1 inhibitor strongly suggested that the stimulation of IL-18 medium, which abolished the effect of 2500 pg/ml IL-18, production by histamine was present in most upstream of the cy- completely inhibited the effects of histamine (100 ␮M) on IL-2, tokine cascade response to histamine in PBMCs and that subse- IFN-␥, and IL-10 production (Table I). The same concentration of quent responses were dependent on the secretion of mature IL-18 histamine (100 ␮M) caused the increase in IL-18 levels, and the from PBMCs. ﬁnal concentration of IL-18 induced by histamine was 2486 pg/ml, On the other hand, the addition of anti-IL-12 mAb concentra- which was comparable to the IL-18 concentration exogenously tion-dependently inhibited the IL-18-induced IFN-␥ production by added in these experiments. Treatment of PBMCs with a up to 77%, suggesting a cooperative effect of IL-18 with endog- caspase-1 inhibitor YVAD-FMK (100 nmol/ml) decreased the enously produced IL-12 on IFN-␥ production (Fig. 5). Higher con- histamine (100 ␮M)-induced IL-18 production to levels below centrations of anti-IL-12 mAb slightly increased the production of the detection limit (Table I). Under this condition, the remain- IL-10, which suggested the minor involvement of IL-12 in IL-18- ing cytokine responses to histamine (100 ␮M) disappeared as in induced inhibition of IL-10 production.

Table I. Effects of anti-IL-18 mAb and caspase-1 inhibitor on cytokine responses induced by histamine and IL-18a

Cytokines (pg/ml)

Additions IL-18 IL-12 IL-2 IFN-␥ IL-10

Untreated ND ND 124 Ϯ 15 32 Ϯ 8 286 Ϯ 35 Histamine (100 ␮M) 2486 Ϯ 175 ND 24 Ϯ 5 165 Ϯ 23 ND IL-18 (2500 pg/ml) – 15 Ϯ 653Ϯ 11 186 Ϯ 31 19 Ϯ 5 IL-18 ϩ anti-IL-18 mAb (10 ng/ml) – ND 132 Ϯ 23* 28 Ϯ 12* 301 Ϯ 19* Histamine ϩ anti-IL-18 mAb (10 ng/ml) ND ND 141 Ϯ 17† 51 Ϯ 16† 274 Ϯ 18† Histamine ϩ caspase-1 inhibitor ND ND 123 Ϯ 8† 36 Ϯ 5† 236 Ϯ 27† (YVAD-FMK, 0.1 ␮mol/ml)

a The results are the means Ϯ SEM of three different donors. *, p Ͻ 0.01 compared with the corresponding value in the presence of IL-18 alone. †, p Ͻ 0.01 as compared with the corresponding value in the presence of histamine alone. 6644 HISTAMINE IS A POTENT INDUCER OF IL-18

FIGURE 5. Effect of increasing concentrations of anti-IL-12 Ab on IFN-␥ and IL-10 responses induced by IL-18. PBMCs (5 ϫ 105/ml) were cultured with 10 ng/ml of IL-18 in the presence of increasing concentrations of anti-IL-12 mAb for 24 h. At the end of the culture, the concentrations of IFN-␥ and IL- 10 in the conditioned media were determined using an ELISA kit as described in Ma- terials and Methods. The results are the means Ϯ SEM of three different donors. p Ͻ 0.05 as compared with the value in ,ء the presence of IL-18 alone. Downloaded from

␥ Effect of histamine on IL-18, IL-12, IL-2, IFN- , and IL-10 motidine and ranitidine, but not by H1 and H3 receptor antagonists, production in T cell/monocyte-rich and B cell-rich populations and the effects of histamine were mimicked by selective H2 recep- We fractionated PBMCs into T cell/monocyte-rich and B cell-rich tor agonists dimaprit and 4-methylhistamine. The relative poten- populations. Using these two cellular preparations, we examined cies of three agonists were similar to those previously reported on http://www.jimmunol.org/ the cellular predominance of histamine-induced cytokine response. H2 receptors in different tissues (39, 40). All these findings as a Table II summarizes the results. The IL-18 response to histamine whole indicated that the effects of histamine on the plural cytokine in the B cell-rich fraction was about one-tenth of that in the T responses were solely mediated by the stimulation of H2 receptors. cell/monocyte-rich fraction. Moreover, no IFN-␥ response to his- Originally, IL-18 was identified as an IFN-␥-inducing factor in tamine was observed in the B cell-rich fraction. Therefore, it was the mouse liver that augmented NK activity in the spleen cells (1). concluded that the cytokine response to histamine mainly occurred The synergistic action of IL-18 with IL-12 has been reported for in the T cell/monocyte-rich fraction. the production of IFN-␥ (10, 12, 13, 41, 42). Yoshimoto et al. (12) demonstrated that IL-12 up-regulated the expression of IL-18 re- Determination of histamine and tele-methylhistamine levels in ceptors in T cells, Th1 cells, and B cells, which enabled the syn- by guest on September 25, 2021 the conditioned media after the incubation of PBMCs with IL-18 ergistic production of IFN-␥. In contrast, IL-18 can stimulate Histamine levels in the conditioned medium in the presence of IFN-␥ production in an IL-12-independent manner in KG-1, a IL-18 (0.1–10 ng/ml) were determined at 2, 12, and 24 h after the monocytic cell line (15). In the present study, the dose-response start of culture. There were no increases in the histamine and tele- curve of IL-18 for the production of IFN-␥ was steep between 0.1 methylhistamine concentrations in the conditioned media at any and 1 ng/ml, suggesting the amplification of the effect of IL-18 in time intervals. this concentration range. In fact, IL-12 production was detected at 1 ng/ml of IL-18 or above. Moreover, the IFN-␥ production in- Discussion duced by IL-18 was inhibited by 80% by the addition of anti-IL-12 In the present study, we revealed that histamine exerted profound Ab, confirming the synergistic action of IL-18 and IL-12 in IFN-␥ effects on the cytokine production in human PBMCs. Histamine- production in human PBMCs. induced responses of IL-18, IL-2, IFN-␥, and IL-10 were all con- In contrast to the IL-18-induced IFN-␥ production, histamine ␥ centration-dependently antagonized by H2 receptor antagonists, fa- induced IFN- production without inducing IL-12 production. The

Table II. Cytokine responses to histamine in T cell/monocyte and B cell fractionsa

Cytokines (pg/ml)

Cell Fraction Histamine (M) IL-18 IL-12 IL-2 IFN-␥ IL-10

T cell ϩ Monocytes 0 ND ND 32 Ϯ 11 ND ND 10Ϫ7 16 Ϯ 7ND13Ϯ 3* 12 Ϯ 2* ND 10Ϫ6 126 Ϯ 16* ND ND 25 Ϯ 12* ND 10Ϫ5 356 Ϯ 54* ND ND 63 Ϯ 8* ND 10Ϫ4 1018 Ϯ 19* ND ND 89 Ϯ 5* ND B cell 0 ND ND ND ND 32 Ϯ 8 10Ϫ7 ND ND ND ND 11 Ϯ 3* 10Ϫ6 ND ND ND ND ND 10Ϫ5 34 Ϯ 4* ND ND ND ND 10Ϫ4 121 Ϯ 47* ND ND ND ND

a The T cell/monocute-rich and B cell-rich fractions were prepared as described in Materials and Methods. The results are the means Ϯ SEM of three different donors. *, p Ͻ 0.01 compared with the corresponding value in the absence of histamine. The Journal of Immunology 6645 concentrations of IL-18 detected in the presence of histamine at 1 In conclusion, we demonstrated that histamine alone is a potent ␮M was above 1 ng/ml, and this concentration was sufficient to inducer of IL-18 and IFN-␥ production. Histamine is a storage induce IL-12 production as shown in Fig. 1. However, histamine amine of mast cells and basophils. The proliferation of the precur- did not induce any IL-12 production at all even at 100 ␮M. This sor of both cells and the production of Ig E Abs are stimulated by strongly suggested that, independent of the IL-18-inducing effect, Th2 cytokines such as IL-4, which are secreted by stimulated mast histamine had strong inhibitory effects on IL-12 production. Thus, cells and basophils (51, 52). Therefore, the effects of histamine on it is quite likely that the IFN-␥ production induced by histamine Th1 cytokine production may function as a negative feedback on was not dependent on IL-12. Recently, two groups have reported excessive Th2 response. A recent report (53) also showed that that IL-12 production was inhibited by histamine through the in- IL-18 with IL-3 can stimulate histamine release from cultured ba- teraction of H2 receptors using human whole blood (43) and hu- sophils, suggesting the presence of a positive feedback system be- man monocyte cultures (44), respectively. Thus it is possible that tween histamine release and IL-18 secretion under certain condi- histamine through the stimulation of H2 receptors inhibited IL-18 tions. Histamine appears to play much more diverse effects on receptor-mediated production of IL-12 in PBMCs. immune cells than expected by modulating the cytokine produc- The pattern of IL-18-induced effects on cytokine production was tion and to be a factor enabling the cross-talk between Th1 and the same as that of histamine except for IL-12 production, strongly Th2 cells. suggesting that the activation cascade after IFN-␥ production was common to both stimulations. Because it was already reported that Acknowledgments IFN-␥ strongly inhibited IL-10 production in PBMCs (45), it is We thank Drs. W. A. M. Duncan and D. J. Durant (The Research Institute, likely that the response of IL-10 was considered to be present in Downloaded from ␥ Smith Kline and French Laboratories) for generously donating dimaprit the downstream IFN- response. Inhibition of IL-2 production by and 4-methylhistamine. histamine and IL-18 was antagonized with anti-IL-18 mAb, suggesting that IL-18 directly inhibited the production of IL-2. Mono- References cyte/macrophage was identified as an IL-18-producing cell (1). Consistent with this finding, histamine-induced IL-18 production 1. Okamura, H., H. Tsutsi, T. Komatsu, M. Yutsudo, A. Hakura, T. Tanimoto, K. Torigoe, T. Okura, Y. Nukada, K. Hattori, et al. 1995. Cloning of a new was observed in the T cell/monocyte-rich fraction but not in the B cytokine that induces IFN-␥ production by T cells. Nature 378:88. http://www.jimmunol.org/ cell-rich fraction. The responses of IFN-␥ and IL-2 to histamine 2. Stoll, S., G. Muller, M. Kurimoto, J. Saloga, T. Tanimoto, H. Yamauchi, ␥ were also present in the T cell/monocyte-rich fraction. Thus, cy- H. Okamura, J. Knop, and A. H. Enk. 1997. Production of IL-18 (IFN- -inducing factor) messenger RNA and functional protein by murine keratinocytes. J. 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Gibson, and It has been suggested that histamine functions as an immuno- T. H. Joh. 1999. Cultures of astrocytes and microglia express interleukin 18. by guest on September 25, 2021 modulator (32, 35). However, the effects of histamine on immune Brain Res. Mol. Brain Res. 67:46. 6. Ghayur, T., S. Banerjee, M. Hugunin, D. Butler, L. Herzog, A. Carter, L. Quintal, cells have proved controversial (35). We showed here that hista- L. Sekut, R. Talanian, M. Paskind, et al. 1997. Caspase-1 processes IFN-␥-in- mine can trigger the IL-18-initiating Th1 cytokine cascade in ducing factor and regulates LPS-induced IFN-␥ production. Nature 386:619. PBMC. Because IL-18 up-regulates perforin-mediated NK activity 7. Gu, Y., K. Kuida, H. Tsutsui, G. Ku, K. Hsiao, M. A. Fleming, N. Hayashi, K. Higashino, H. Okamura, K. Nakanishi, et al. 1997. Activation of interferon-␥ (46) and histamine was reported to enhance NK cell activity (47), inducing factor mediated by interleukin-1␤ converting enzyme. 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Murine macro- metabolite tele-methylhistamine in the conditioned media of PB- phages secrete interferon ␥ upon combined stimulation with interleukin (IL)-12 MCs in the presence of IL-18, the induction of histidine decarbox- and IL-18: a novel pathway of autocrine macrophage activation. J. Exp. Med. ylase was reported in monocyte/macrophage (26) and T lympho- 187:2103. ␣ 14. Dinarello, C. A. 1999. IL-18: a TH1-inducing, proinflammatory cytokine and cytes (27) by LPS, IL-1, and TNF- (50). Such inducible new member of the IL-1 family. J. Allergy Clin. Immunol. 103:11. histamine appeared to be released after the synthesis without en- 15. Kohka, H., T. Yoshino, H. Iwagaki, I. Sakuma, T. Tanimoto, Y. Matsuo, tering into the stable storage pool (26, 27, 50). Therefore, it is M. Kurimoto, K. Orita, T. Akagi, and N. Tanaka. 1998. 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