Histamine inhibits high mobility group box 1-induced adhesion molecule expression on human monocytes

Hideo Takahashi a,n, Hiroshi Sadamori b, Kiyoshi Teshigawara c, Atsuko Niwa a, Keyue Liu c, Hidenori Wake c, Shuji Mori d, Tadashi Yoshino e, Masahiro Nishibori c

Abstract

Cell–cell interaction through binding of adhesion molecules on monocytes to their ligands on T-cells plays roles in cytokine production and lymphocyte proliferation. High mobility group box 1 (HMGB1), an abundant and conserved nuclear protein, acts in the extracellular environment as a primary proinflammatory signal. HMGB1 induces expression of intercellular adhesion molecule (ICAM), B7.1, B7.2 and CD40 on monocytes, resulting in production of interferon (IFN)-γ and tumor necrosis factor (TNF)-α production and lymphocyte proliferation in human peripheral blood mononuclear cells (PBMCs). Histamine inhibits pro-inflammatory cytokine production via histamine H2-receptors; however, it is not known whether histamine inhibits HMGB1 activity. This study was designed to study the inhibitory effect of histamine on HMGB1 activity. We examined the effect of histamine on HMGB1-induced expression of ICAM-1, B7.1, B7.2 and CD40 on monocytes, production of IFN-γ and TNF-α and lymphocyte proliferation in PBMCs. Histamine inhibited HMGB1 activity in a concentration-dependent manner. The effects of histamine were partially ablated by the H2-receptor antagonist, famotidine, and mimicked by the H2/H4-receptor agonists, dimaprit and 4-methylhistamine. Histamine induced cyclic adenosine monophosphate (cAMP) production in the presence and absence of HMGB1. The effects of histamine were reversed by the protein kinase A (PKA) inhibitor, H89, and mimicked by the membrane-permeable cAMP analog, dibutyryl cAMP (dbcAMP), and the adenylate cyclase activator, forskolin. These results together indicated that histamine inhibited HMGB1 activity

Keywords:
High mobility group box 1
Histamine H2 receptor
Monocyte
Adhesion molecule
Cyclic adenosine monophosphate

1. Introduction

It has been known that the ubiquitous nuclear protein, high mobility group box 1 (HMGB1), modifies DNA structure to facilitate transcription, replication and repair (Bustin, 1999). An endogenous danger-associated molecular pattern protein (DAMP), which is released from stressed or injured cells, is the initial trigger for an inflammatory response. Recently, it has been reported that one of the most well-known DAMPs, namely the afore-mentioned HMGB1, is passively released from necrotic cells (Scaffidi et al., 2002) and secreted from stressed monocytes/ macrophages (Gardella et al., 2002). Many studies have reported that extracellular HMGB1 has pro-inflammatory and immuno-stimulatory properties and contributes to the pathogenesis of chronic inflammatory and autoimmune diseases, including hepatitis (Albayrak et al., 2010), rheumatoid arthritis (Kokkola et al., 2002), inflammatory bowel disease (McDonnell et al., 2011), acute lung inflammation (Abraham et al., 2000) and atherosclerosis (Porto et al., 2006).
Monocyte-derived costimulatory signals play roles in eliciting maximal T-cell proliferation, and cytokine production, lowering the concentration of antigen required for stimulation and promoting more sustained signaling from the T-cell receptor. The interaction of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2 and CD40 on monocytes with their ligands on T-cells produces important costimulatory signals (Dustin and Springer, 1989; Greenfield et al., 1998). It has been reported that HMGB1 induces inflammatory responses, including maturation and migration of monocytes/macrophages (Rauvala and Rouhiainen, 2010), leading to activation of naïve T-cells in the promotion and induction of Th1 responses and to clonal expansion of antigen-specific T-cells (Messmer et al., 2004; Dumitriu et al., 2005). It is reported that HMGB1 induces production of tumor necrosis factor (TNF)-α, but not of interleukin (IL)-10 or IL-12, in normal human peripheral blood mononuclear cells (PBMCs) (Andersson et al., 2000). In a previous study, we found that HMGB1-induced pro-inflammatory cytokine production depended on an intimate cellular interplay between monocytes and T-cells in human PBMCs (Takahashi et al., 2013).
It has been reported that histamine modulates cytotoxic T-cell activity (Khan et al., 1989), NK-cell activity (Hellstrand et al., 1994) and cytokine production in human PBMCs (van der Pouw Kraan et al., 1998; Elenkov et al., 1998). Histamine activities depend on the stimulation of histamine H1-, H2-, H3- and H4-receptors (van der Pouw Kraan et al., 1998; Elenkov et al., 1998). Immunoregulatory effects of histamine are reported to depend on the stimulation of histamine H2-receptors (van der Pouw Kraan et al., 1998; Elenkov et al., 1998; Hough, 2001). Histamine H2-receptor stimulation induces the activation of adenylate cyclase and the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway in monocytes (Shayo et al., 1997). However, little is known about the effect of histamine on HMGB1-induced activity in monocytes.
In the present study, we examined the effect of histamine on HMGB1-induced expression of ICAM-1, B7.1, B7.2 and CD40, the production of interferon (IFN)-γ and TNF-α and lymphocyte proliferation in PBMCs.

2. Materials and methods

2.1. Reagents and drugs

Recombinant human (rh) HMGB1 was produced as described previously (Wake et al., 2009a). In brief, complementary DNA (cDNA) encoding full-length HMGB1 was amplified by polymerase chain reaction (PCR) from human microvascular endothelial cell cDNA. The PCR product was subcloned into a pGEX-6p-1 vector (GE Healthcare, Little Chalfont, England) to generate a glutathione S-transferase (GST) fusion protein. Sf9 insect cells (Invitrogen Life Technologies, NY) were transformed with the recombinant plasmid and incubated overnight at 37 1C in Overnight Express Instant TB Medium (Merck, San Diego, CA) to express recombinant GST-HMGB1. A Sf9 cell extract containing GST-HMGB1 fusion proteins was incubated with glutathioneSepharose 4B for 1 h at room temperature. After washing, the gel bed was incubated with PreScission protease for 3 h at 4 1C. After a brief centrifugation, the supernatant containing HMGB1 with the GST tag removed was collected and purified by gel filtration chromatography using TSK-gel 3000SWXL (Tosoh, Tokyo, Japan). Purified rhHMGB1 protein was identified by Western blotting (Wake et al., 2009a) with a rat anti-human HMGB1 monoclonal Ab (mAb). The lipopolysaccharide (LPS) content of the purified rhHMGB1 was o2.0 pg/μg protein.
Histamine dihydrochloride was purchased from Nacalai Tesque Inc. (Kyoto, Japan). Dimaprit dihydrochloride and 4-methylhistamine dihydrochloride (4-MH) were gifts from Drs. WAM Duncan and DJ Durant (The Research Institute, Smith Kline and French Laboratories, Welwyn Garden City, Herts, UK). d-Chlorpheniramine maleate, ranitidine and famotidine were provided by Yoshitomi Pharmaceutical Co. Ltd. (Tokyo, Japan), Glaxo Japan (Tokyo, Japan) and Yamanouchi Pharmaceutical Co. Ltd. (Tokyo, Japan), respectively. Thioperamide hydrochloride was provided by Eisai Co. Ltd. (Tokyo, Japan). Dibutyryl cAMP (dbcAMP) and forskolin were purchased from Wako Co., Ltd. (Tokyo, Japan). H89 was purchased from Sigma Chemical (St. Louis, MO, USA).

2.2. Isolation of PBMCs

Normal human PBMCs were obtained from ten healthy volunteers after acquiring Institutional Review Board approval (Okayama Univ. IRB No.106). Each 20–50 ml peripheral blood sample was withdrawn from a forearm vein, after which PBMCs were prepared and monocytes were separated from the PBMCs by counterflow centrifugal elutriation as previously described (Takahashi et al., 2002; Takahashi et al., 2003).

2.3. Flow cytometric analysis for adhesion molecule expression

For flow cytometric analysis, fluorescein isothiocyanate (FITC)-conjugated mouse IgG1 mAb against human ICAM-1/ CD54 and R-Phycoerythrin (PE)-conjugated anti-human CD14 mAb were purchased from DAKO (Glostrup, Denmark). FITCconjugated mouse IgG1 mAb against human B7.2 and CD40 were purchased from Pharmingen (San Diego, CA), and FITCconjugated IgG1 class-matched control was purchased from Sigma Chemical. FITC-conjugated mouse anti-mouse ICAM-1 mAb was purchased from DAKO. Changes in the expression of the human leukocyte antigens ICAM-1, B7.1, B7.2 and CD40 on monocytes (CD14) was examined by multi-color flow cytometry using a mixture of anti-CD14 Ab with anti-ICAM-1, anti-B7.1, anti-B7.2 or anti-CD40 Ab. PBMCs (4 106/ml) were incubated with 0.1–100 μg/ml HMGB1 and 0.1–100 μM histamine for 24 or 48 h at 37 1C in RPMI 1640 (Nissui Co. Ltd., Tokyo, Japan) supplemented with 10% heat-inactivated fetal calf serum (FCS), 20 μg/ml kanamycin, 100 μg/ml streptomycin and penicillin, and 5 105/ml cultured cells were then prepared for flow cytometric analysis as previously described (Takahashi et al., 2002; Takahashi et al., 2003) and analyzed with a FACSCalibur (BD Biosciences, San Jose, CA). The data were processed using the CELL QUEST program.

2.4. Enzyme-linked immunosorbent assay

PBMCs (4 106/ml) were used for assessment of IFN-γ and TNFα production. After incubation at 24 h at 37oC in a 5% CO2/air mixture, cell-free supernatants were assayed for IFN-γ and TNF-α proteins by enzyme-linked immunosorbent assay (ELISA) using the multiple Abs sandwich principle (R&D Systems, Minneapolis, MN). The ELISA detection limit for both IFN-γ and TNF-α was 10 pg/ml.

2.5. Proliferation assay

PBMCs (4 106/ml) were treated with various reagents and incubated for 24 h at 37 1C in RPMI 1640 supplemented with 10% heat-inactivated FCS, 20 μg/ml kanamycin, 100 μg/ml streptomycin and penicillin, during which they were pulsed with [3H]-thymidine (3.3 Ci/well) for the final 16 h. The cells were then dispensed into 96-well microplates, 200 μl/well, resulting in 1 μCi [3H]thymidine per well, and harvested with a Micro-Mate 196 Cell Harvester (Perkin Elmer Life Science Inc., Boston, MA, USA). Thymidine incorporation was measured with a Matrix 9600 βcounter (Perkin Elmer Life Science Inc., Yokohama, Japan).

2.6. Measurement of cAMP production in monocytes

Monocytes at 1 106 cells/ml were incubated at 37 1C in a 5% CO2/air mixture under different conditions. When the effects of histamine receptor antagonists were examined, the antagonists were added to the media 30 min before histamine addition. HMGB1 and histamine were simultaneously added to the media. After 24 h, cells (2 105cells/200 μl/well) were supplemented with trichloroacetic acid to a final concentration of 5% and 3-isobutyl-1methylxanthine, an inhibitor of phosphodiesterase, at 100 μM and frozen at 80 1C. Frozen samples were subsequently sonicated and assayed for cAMP using a cAMP enzyme immunoassay kit (Cayman Chemical, Ann Arbor, MI) according to the manufacturer’s instructions, for which no acetylation procedures were performed. The results are expressed as the mean7standard error of the mean (S.E.M.) for five donors.

2.7. Statistical analysis

Statistical significance was evaluated using ANOVA followed by a Dunnet’s test. A probability value o0.05 was considered to indicate statistical significance. Each data point was expressed as the mean 7 S.E.M. of triplicate determinations from five donors.

3. Results

3.1. Effects of histamine on HMGB1-induced expression of ICAM-1, B7.1, B7.2 and CD40 on monocytes, the production of IFN-γ and TNF-α and lymphocyte proliferation in PBMCs

HMGB1, at 10 μg/ml, significantly induced expression of ICAM1, B7.1, B7.2 and CD40, production of IFN-γ and TNF-α and lymphocyte proliferation at 16 h and, thereafter, up to 24 and 48 h (Takahashi et al., 2013). Adhesion molecule expression, cytokine production and lymphocyte proliferation increased at 1 μg HMGB1/ml and continued to increase up to 10 and 100 μg HMGB1/ml. As shown in Fig. 1, we observed the effects of histamine, at concentrations ranging from 0.1 to 100 μM, on expression of ICAM-1, B7.1, B7.2 and CD40, the production of IFN-γ and TNF-α and lymphocyte proliferation in the presence or absence of 10 μg/ml HMGB1 at 24 h. Histamine inhibited HMGB1 activities in a concentration-dependent manner. IC50 values for the inhibitory effect of histamine on expression of ICAM-1, B7.1, B7.2 and CD40, the production of IFN-γ and TNF-α and lymphocyte proliferation in the presence of HMGB1 were 0.8, 0.7, 1, 0.8, 1, 1 and 1 μM, respectively. In the absence of HMGB1, histamine induced the production of IFN-γ and TNF-α, but had no effect on adhesion molecule expression and lymphocyte proliferation.

3.2. Involvement of H2-receptor in the actions of histamine

To determine the histamine receptor subtypes involved in mediating the effects of histamine on expression of ICAM-1, B7.1, B7.2 and CD40, production of IFN-γ and TNF-α and lymphocyte proliferation in the presence of HMGB1, the activity of a histamine H1-receptor antagonist, d-chlorpheniramine, a histamine H2-receptor antagonist, famotidine, and a histamine H3/H4-receptor antagonist, thioperamide, at concentrations ranging from 0.1 to 100 μM on adhesion molecule expression, cytokine production and proliferation were examined in the presence of histamine at 10 μM (Fig. 2). Famotidine inhibited the action of histamine in a concentration-dependent manner, but d-chlorpheniramine and thioperamide had no effect. Another histamine H2-receptor antagonist, ranitidine, exerted a substantially similar effect to famotidine (data not shown).
As shown in Fig. 3, the effects of histamine H2/H4-receptor agonists, dimaprit and 4-MH (Parsons et al., 1977), at concentrations ranging from 0.1 to 100 μM were determined in the presence of HMGB1 at 10 μg/ml. Both dimaprit and 4-MH inhibited expression of ICAM-1, B7.1, B7.2 and CD40, production of IFN-γ and TNF-α and lymphocyte proliferation in a concentrationdependent manner. The potency and efficacy of two agonists were quite similar to those of histamine in each response. Moreover, we found that a histamine H1-agonist, 2-(2-pyridyl) ethylamine dihydrochloride (Durant et al., 1975), and a histamine H3-agonist, (R)α-methylhistamine dihydrochloride (Arrang et al., 1987), had no effect on adhesion molecule expression, cytokine production and lymphocyte proliferation induced by HMGB1 (data not shown).

3.3. Effects of histamine on the production of cAMP in monocytes in the presence or absence of HMGB1

The effects of histamine at 100 μM on the production of intracellular cAMP in monocytes isolated from PBMCs in the presence or absence of 10 μg/ml HMGB1 were determined (Fig. 4). Histamine induced the production of cAMP in monocytes with a peak 30 min after stimulation. The presence of HMGB1 did not influence the production of cAMP induced by histamine. The histamine H2-receptor antagonist, famotidine (at 100 μM) inhibited the effect of histamine on the production of cAMP (Fig. 4). Also, the histamine H2/H4-receptor agonist, dimaprit (at 100 μM) induced the production of cAMP (Fig. 4).

3.4. Involvement of cAMP in the action of histamine

To investigate the involvement of the cAMP/PKA pathway in the action of histamine, the effects of a PKA inhibitor, H89, at concentrations ranging from 0.1 to 100 μM on the action of histamine at 10 μM were determined (Fig. 5). In the absence of histamine, the PKA inhibitor had no effect on adhesion molecule expression, cytokine production and lymphocyte proliferation. H89 reversed the inhibitory effect of histamine on expression of ICAM-1, B7.1, B7.2 and CD40, production of IFN-γ and TNF-α and lymphocyte proliferation in the presence of 10 μg/ml HMGB1. As shown in Fig. 6, the effects of a membrane-permeable cAMP analog, dbcAMP, and an adenylate cyclase activator, forskolin, at concentrations ranging from 0.01 to 10 μM on expression of ICAM1, B7.1, B7.2 and CD40 on monocytes, production of IFN-γ and TNFα and lymphocyte proliferation in PBMCs were examined. Both dbcAMP and forskolin inhibited HMGB1-induced adhesion molecule expression, cytokine production and lymphocyte proliferation in a concentration-dependent manner.

3.5. Effects of histamine on expression of CD14, TLR-2, TLR-4 and RAGE on monocytes

The receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)-2 and TLR-4 are receptors for HMGB1 (Hori et al., 1995; Park et al., 2004; van Beijnum et al., 2008). In the previous study, the effect of incubation with 0.1–100 μg/ml HMGB1 on RAGE, TLR-2 and TLR-4 expression on monocytes in human PBMCs was determined after a 24 h incubation (Takahashi et al., 2013). HMGB1 increased RAGE expression in a concentration-dependent manner, but had no effect on TLR-2 or TLR-4 expression. The expression of increased at 1 μg HMGB1/ml and continued to increase up to 10 and 100 μg HMGB1/ml. 10 μg HMGB1/ml enhanced the expression of CD14 (Fig. 7).
As shown in Fig. 7A, we observed the effects of histamine, at concentrations ranging from 0.1 to 100 μM, on expression of RAGE and CD14 in the presence or absence of 10 μg/ml HMGB1 at 24 h. Histamine inhibited expression of RAGE and CD14 in a concentration-dependent manner. The histamine H2-receptor antagonists, famotidine (Fig. 7B), as well as famotidine (data not shown), inhibited the action of histamine, while d-chlorpheniramine and thioperamide had no effect (data not shown). Moreover, histamine H2/H4-receptor agonists, dimaprit and 4-MH inhibited expression of RAGE and CD14 (Fig. 7C).

4. Discussion

A pro-inflammatory mediator HMGB1, which is secreted by activated monocytes/macrophages, is reported to induce inflammation and injury (Wang et al., 1999). The expression of histamine has been observed in monocytes/macrophages, suggesting that histamine plays roles in the regulation of basic biological cell processes (Sasaguri and Tanimoto, 2004). In the present study, we clearly demonstrated, for the first time, that histamine inhibited HMGB1-induced adhesion molecule expression on monocytes, cytokine production and lymphocyte proliferation in human PBMCs (Fig. 1), indicating that HMGB1induced inflammation and injury is modulated by an endogenous mediator, histamine. The effects of histamine were inhibited by the histamine H2-receptor antagonist but not the histamine H1-antagonist or the H3/H4-receptor antagonist (Fig. 2). The histamine H2/4-receptor agonists mimicked the effects of histamine (Fig. 3). The IC50 values of histamine and histamine H2/H4-receptor agonists to prevent the upregulation of adhesion molecule expression and cytokine production were consistent with the affinity of those agonists to typical histamine H2-receptors (Johnson 1982; Elenkov et al., 1998; Kohka et al., 2000; Morichika et al., 2003: Takahashi et al., 2002), indicating that the inhibitory effects of histamine depended on the stimulation of histamine H2-receptors. As shown in Figs. 4, 5 and 6, the findings, at least, suggested the involvement of the cAMP/PKA pathway in the effects of histamine.
In the previous study, we suggested that RAGE and TLR-4 are involved in the pathogenesis of a wide range of inflammatory disorders via recruitment of ligands (Takahashi et al., 2013). As shown in Fig. 7, histamine inhibited HMGB1-induced RAGE expression on monocytes through stimulation of histamine H2-receptors, indicating that the inhibitory effect of histamine on HMGB1 activity depends on the regulation of RAGE expression.
We found a similar pattern of effects of histamine on advanced glycation end products (AGEs)-, LPS- and IL-18-induced activation of monocytes in human PBMCs via H2-receptors (Morichika et al., 2003; Takahashi et al., 2002; Wake et al., 2009b). IL-18 is reported to induce expression of ICAM-1, B7.1, B7.2 and CD40 on monocytes (Takahashi et al., 2002; Takahashi et al., 2003). While HMGB1 or AGEs do not induce production of IL-18 in PBMCs (Takahashi et al., 2013; Takahashi et al.,2009), histamine induces production of IL-18 via the histamine H2-receptor and the cAMP/PKA pathway in monocytes (Takahashi et al., 2006). Whereas the amount of IL-18 production induced by histamine at 100 μM in the absence of HMGB1 was 2.5 ng/ml (Takahashi et al., 2006), that in the presence of HMGB1 was under the detection limit (10 pg/ml) (data not shown). Exogenously added IL-18 at 10 ng/ml significantly inhibited the effects of histamine on HMGB1 activity (Takahashi et al.,2009). Moreover, it is reported that histamine alters the Th1/Th2 balance at the level of antigen presenting cells, Th1 and Th2 cells, or directly on effector cells (Elenkov et al., 1998). These results indicated an adverse effect of histamine. Thus, there may be a common pathway triggered by LPS, IL-18, AGEs and HMGB1 that is regulated by the histamine H2-receptor-cAMP/PKA system. Further work is necessary to clarify this issue.
Macrophages/monocytes and T-cells play key roles in the immune responses of patients with inflammatory diseases; however, little is known regarding the mechanism underlying the effect of histamine on HMGB1 activities in human PBMCs. Intrahepatic recruitment of macrophages/monocytes and T-cells is reported to contribute to HMGB1-induced inflammation in an HBV-based mouse model of hepatitis (Sitia et al., 2007). In contrast, we found that endogenously produced histamine in Kupffer cells/macrophages plays a very important role in preventing an excessive innate immune response in endotoxin-induced fulminant hepatitis through the stimulation of histamine H2receptors (Yokoyama et al., 2004). Moreover, we found that HMGB1 exerted proatherogenic effects, augmenting lesion development by stimulating macrophage migration, modulating proinflammatory mediators, and encouraging the accumulation of immune and smooth muscle cells (Kanellakis et al.,2011). Histidine decarboxylase, which produces histamine from L-histidine, is detected in monocytes/macrophages located in the arterial intima in human atherosclerotic lesions (Higuchi et al., 2001). The resultant production of histamine may regulate vascular contraction (Tanimoto et al., 2007), indicating the modulatory effects of histamine on micro-inflammation in atherosclerotic intima. Thus, locally produced histamine may exert inhibitory influence on the activation of monocytes/macrophages and T-cells. Such a possibility should be evaluated by an in vivo hepatitis and atherosclerotic model.

5. Conclusions

Histamine inhibited HMGB1-induced expressions of ICAM-1, B7.1, B7.2 and CD40, production of IFN-γ and TNF-α and lymphocyte proliferation via histamine H2-receptors. Histamine inhibition of cellular interplay between monocytes and T-cells may reduce cytokine production and lymphocyte proliferation (Fig. 8). Through the inhibition of HMGB1 effects on monocytes, the stimulation of histamine H2-receptors may partially contribute to regulating the development of inflammatory diseases.

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