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TOXICOLOGY
Department of Pharmacology and Therapeutics, Sherrington Buildings, Ashton Street, University of Liverpool, Liverpool, United Kingdom (E.M.C., J.F., K.L.M., J.L.M., B.K.P., D.J.N.); and Safety and Environmental Assurance Centre Toxicology Laboratory, Unilever Research, Colworth House, Bedfordshire, United Kingdom (C.K.P., D.J.L., D.A.B.)
Received September 11, 2006; accepted November 13, 2006.
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Abstract |
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). On contact, pPD can produce severe allergic dermatitis: a delayed cell-mediated immune response that causes skin erythema and edema (Smith Pease, 2003).
It is well established that for the development of contact dermatitis, pPD must provide chemical signals that activate and thereby convert dendritic cells from functionally immature antigen recognition cells into mature and potent antigen-presenting cells and act as an antigenic stimuli and thereby stimulate specific effector T-cells (Matzinger, 1994; Curtsinger et al., 1999, 2003). The effects of pPD on immune cells are thought to derive from the chemical's instability, autoxidation in solution results in the formation of an electrophilic quinonediimine intermediate, which is susceptible to sequential self-conjugation. An end product of these oxidoconjugation reactions is the trimer Bandrowski's base (BB) (Fig. 1).
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) and others (Ashikaga et al., 2002; Aeby et al., 2004; Toebak et al., 2006) have focused on the ability of pPD to activate dendritic cells. In these experiments, in vitro exposure of dendritic cells to pPD, pPD analogs, and BB resulted in functional maturation as measured by increased expression of cell surface receptors and/or cytokine synthesis. Moreover, Krasteva et al. (1996) and Rougier et al. (2000) used these findings to develop a T-cell culture system for evaluation of chemical sensitization potential. In this study, both pPD and BB were able to induce a significant T-cell response in certain individuals. It is noteworthy that the fate of test chemicals within these in vitro cell systems has not been explored, and as such, the nature of the chemical that interacts with immune cells is not known. Thus, the aim of these studies was to use a combined chemical and cellular immunological approach to explore the relationship between pPD autoxidation and activation of human monocyte-derived dendritic cells. We show that exposure of dendritic cells to nontoxic concentrations of pPD, but not BB, results in functional maturation. Of particular importance was the use of the antioxidant glutathione, which prevented the oxidation of pPD to BB but did not inhibit covalent binding of pPD to dendritic cell protein or pPD-mediated dendritic cell activation.
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Materials and Methods |
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pPD was obtained from Sigma Chemical Co. (Poole, Dorset, U.K.). Bandrowski's base was obtained ICN Biomedicals Inc. (Aurora, OH). [14C]pPD (specific activity, 60 mCi/mmol; radiochemically homogeneous as determined by HPLC) was synthesized by Amersham Biosciences UK Limited (Bucks, UK). Stock solutions (1 mg/ml) were dissolved in cell culture medium/dimethyl sulfoxide (4:1, v/v) and diluted as required. Chromatography-grade solvents were products of Fisher Scientific (Loughborough, Leicestershire, UK). All other reagents were obtained from Sigma Chemical Co.
Subjects. Eight healthy subjects (four men and four women with no known history of hair dye exposure) with a median age of 28 years (range, 24–35) were enrolled for the study. The study was approved by the local ethics committee, and each subject provided written informed consent to participate.
Generation of Human Monocyte-Derived Dendritic Cells. Lymphocytes were isolated from heparinized freshly drawn blood of eight healthy volunteers (by density centrifugation using Lymphoprep; Greiner Bio-One, Inc., Longwood, FL). Isolated cells (2 x 106) were dispensed into 24-well cell culture plates in culture medium and incubated at 37°C for 4 h. After two washes, adherent cells were resuspended in medium containing the cytokines interleukin-4 (300 U/ml) and granulocyte/macrophage colony-stimulating factor (600 U/ml) (PeproTech, London, UK). Half the culture medium was changed on days 1, 3, and 5. On day 6, flow cytometric analysis was used to confirm that dendritic cells expressed high levels of CD11c but low and LPS-inducible levels of CD40, CD80, CD83, and CD86. Data were analyzed by generating a gate around the dendritic cell population based on the side scatter/forward scatter profile.
Stimulation of Dendritic Cells with p-Phenylenediamine and Bandrowski's Base. Functionally immature dendritic cells (on day 6 of culture) were incubated with pPD and BB (1, 5, 10, 20, 30, 50, or 100 µM) for 16 h at 37°C. Because the primary pPD oxidation product, pPD quinonediimine, is not available commercially, certain experiments were performed with pPD in the presence of glutathione (1 mM), which blocks the generation of BB, but not covalent binding (see below). All stock solutions were prepared, diluted, and added to dendritic cells without delay. Possible endotoxin contamination was assessed for using polymyxin B.
Untreated as well as stimulated dendritic cells were washed repeatedly and stained with FITC-conjugated mAbs to CD40, CD80, CD83, CD86, and FITC anti-human HLA-DR (Serotec, Oxford, UK) for 30 min on ice. Cells were washed repeatedly and analyzed using flow cytometry (Coulter Epics XL software; Beckman Coulter, Fullerton, CA). A minimum of 2000 events per sample were analyzed. The fluorescence intensity of stimulated dendritic cells was compared directly with dendritic cells treated with solvent alone.
Assessment of Dendritic Cell Viability with p-Phenylenediamine. In initial experiments, dendritic cell viability following pPD treatment (10–2500 µM) was assessed by trypan blue exclusion using established methods. To evaluate the mechanism of dendritic cell killing, apoptosis and necrosis were measured simultaneously using annexin V/propidium iodide dual staining methodology with flow cytometric analysis (Vermes et al., 1995). Annexin V binds to phosphatidylserine residues expressed on the surface of apoptotic cells, whereas propidium iodide is a membrane-impermeable fluorescent dye that binds to DNA of cells killed by necrosis. A combination of these two characteristics permits simultaneous detection of viable, apoptotic, and necrotic cells.
Assessment of Intracellular Dendritic Cell Glutathione Levels with p-Phenylenediamine. Dendritic cells were incubated with pPD (10–250 µM) for 16 h. Cells were then washed and lysed with 10 mM HCl, and an aliquot was taken for protein content determination by the method of Bradford (1976). Total and oxidized glutathione levels were determined by a microtiter plate assay according to the method of Vandeputte et al. (1994). Reduced glutathione levels were determined by subtracting oxidized glutathione from total glutathione and are expressed as nanomoles of glutathione per milligram of protein.
Allogenic Mixed Lymphocyte Reaction with p-Phenylenediamine. To evaluate the ability of dendritic cells to stimulate lymphocyte proliferation, pPD- and BB-treated and -untreated dendritic cells (culture conditions and methods as described above) were washed repeatedly, irradiated (6000 rads; 5 x 103 to 5 x 104), and cocultured with freshly isolated allogeneic lymphocytes (from healthy volunteers; 50 x 104/well) in 96-well round-bottom tissue culture plates for 5 days. [3H]Methylthymidine (1 µCi) was added to each well for the final 16 h of the incubation, and incorporated radioactivity was counted on a 
-counter. Results are shown as mean counts per minute of triplicate cultures.
Determination of the Chemical Fate of p-Phenylenediamine. [14C]pPD (50 and 500 µM[1 µCi]; ±glutathione [1 mM]) was incubated with cell culture medium at 37°C for up to 16 h in the presence and absence of dendritic cells. At 0, 4, and 16 h, 100-µl aliquots were taken and analyzed by liquid chromatography-mass spectrometry. The eluent was delivered by Jasco PU980 pumps (Great Dunmow, Essex, UK). Analytes in the eluate were monitored with a Jasco UV-975 spectrophotometer (
= 254 nm). Radiolabeled analytes were quantified using a Radiomatic Flo-One A-250 flow detector (Perkin Elmer, Pangbourne, Berkshire, UK). The eluate was mixed with Ultima-Flo AP scintillant at a rate of 1 ml/min. The split flow of eluate to the mass spectrometer was 
50 µl/min. Mass spectra were acquired between m/z 50 and 1050 Micromass with a Quattro II instrument (Waters Corp., Manchester, UK) at 1 scan/5 s. The source temperature was 80°C, the capillary voltage was 3.9 x 103, and the standard cone voltage was 30 V. Data were processed via MassLynx 3.5 software (Micromass Ltd., Manchester, UK). Aliquots of the solution were eluted without treatment from a Zorbax SB-C18 column (250- x 46-mm i.d.; Phenomenex, Macclesfield, Cheshire, UK) at room temperature with a gradient of methanol (5% for 5 min; 5–60% over 15 min) in 10 mM ammonium acetate, pH 6.9; the flow rate was 0.9 ml/min.
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; Pirmohamed et al., 1995). Cellular and serum protein were separated by centrifugation and subsequently extracted using 100% acetonitrile (2 ml x one wash and 1 ml x three washes). Protein was dissolved in sodium hydroxide (1 M; 2 ml), and aliquots (100 µl) were taken for quantification of bound radioactivity. Protein concentration was measured according to the method of Bradford (1976). Statistical Analysis. Statistical significance was determined using the Mann Whitney U test, Friedman test, and paired sample Student's t test, as deemed appropriate, accepting p < 0.05 as significant. All fluorescence-activated cell sorting data presented diagrammatically are represented as percentage increase in median fluorescence intensity at the specified range of concentrations.
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Results |
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BB had no effect on CD40 expression. Moreover, exposure of dendritic cells to pPD or BB (1–100 µM) did not significantly alter expression of the cell surface costimulatory receptors CD80, CD83, and CD86.
LPS served as a positive control for dendritic cell maturation (Gosset et al., 2003). LPS treatment consistently induced increased expression of CD40, CD80, CD83, and CD86.
Dendritic Cell Toxicity with p-Phenylenediamine. The viability of dendritic cells in the presence of pPD was investigated initially by cell counting using trypan blue. pPD treatment at concentrations associated with increased CD40 expression (5–50 µM) did not significantly alter dendritic cell viability. A concentration-dependent increase in cell death was observed when dendritic cells were incubated with higher pPD concentrations (250 µM and above; Fig. 3a). Similar data were obtained with flow cytometric analysis of pPD-treated dendritic cells. A significant increase in cell death was obtained at pPD concentrations of 100 µM and above (Fig. 3b).
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Conversion of p-Phenylenediamine to Bandrowski's Base in Culture Does Not Cause Increased Dendritic Cell CD40 Expression. The stability of pPD was investigated using parallel radiometric HPLC and liquid chromatography-mass spectrometry. Initial experiments revealed that pPD ([M + 1]+ at m/z 109; Rt, 7.5 min) in cell culture medium alone was converted to BB (m/z, 319; Rt, 22.5 min) and an unidentified product yielding an ion with a mass ratio of 137 (Rt, 11.2 min) within 16 h. The addition of dendritic cells did not significantly alter the profile, nor the extent of pPD oxidation or the products formed (Fig. 4a). The addition of glutathione (1 mM) to cell culture media was found to completely inhibit the formation of BB (Fig. 4a) at a pPD concentration of 50 µM. It is noteworthy that the addition of glutathione (1 mM) did not inhibit LPS-mediated (data not shown) or pPD-mediated (Fig. 4b) increased dendritic cell CD40 expression in all eight individuals.
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p-Phenylenediamine Binds Irreversibly to Dendritic Cells in the Presence and Absence of Glutathione. [14C]pPD was found to bind irreversibly to both dendritic cell and serum protein during the 16-h incubation, as revealed by detection of radiolabeled moieties following exhaustive solvent extraction (Fig. 4c). In the presence of glutathione, which inhibits BB formation, the level of irreversible binding of pPD to dendritic cell or serum protein was not significantly different.
Increased Dendritic Cell Surface Expression of MHC Class II with p-Phenylenediamine Is Associated with Enhanced Stimulation of Allogeneic T-Cells. Because increased expression of CD40 does not guarantee immunostimulatory effects on T-cells, we also examined MHC class II expression and the ability of pPD-treated dendritic cells to stimulate allogeneic lymphocyte proliferation. As shown in Fig. 5, dendritic cells cultured with LPS or pPD showed increased MHC class II expression and a higher lymphocyte stimulatory efficiency compared with immature vehicle-treated cells.
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Discussion |
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). Skin-resident dendritic cells are potent antigen-presenting cells and immunological sentinels that respond following allergen exposure by functional maturation and migration toward draining lymph nodes (Cumberbatch et al., 2005). Dendritic cells exhibit a unique ability to activate naive T cells depending on their maturational stage. Immature dendritic cells that bear low levels of costimulatory molecules, such as CD40, CD80, and CD86, show modest ability to activate T cells. Upon encountering a foreign antigen and/or "danger signals," dendritic cells secrete cytokines, and the expression of costimulatory molecules is rapidly up-regulated. These so-called functionally mature dendritic cells exhibit a potent ability to activate T cells (Banchereau and Steinman, 1998; Lanzavecchia and Sallusto, 2001). Several groups have shown functional maturation of dendritic cells and dendritic-like cell lines in vitro following exposure to chemical allergens (Rougier et al., 2000; Hulette et al., 2002; Aiba et al., 2003; Straube et al., 2005; Toebak et al., 2006). Despite this, the nature of the interaction between the chemical and dendritic cell proteins and how this leads to altered dendritic cell function is not fully understood. The aims of the current investigation were to determine whether exposure of human dendritic cells to pPD is associated with functional maturation and the nature of the chemical that interacts with dendritic cells.
Recently, Hulette et al. (2005) have shown that pPD concentrations (above 2.5 mM) that are associated with significant cell death stimulate dendritic cell maturation, as assessed by up-regulation of CD86 expression; presumably via a classical "danger" response (Matzinger, 1994) and the recognition of released endogenous signaling molecules (Gallucci et al., 1999; Shi et al., 2003). Similar pPD concentrations (2.3 mM) also induce signal transduction events, including tyrosine phosphorylation (Bruchhausen et al., 2003). Moreover, Toebak et al. (2006) have shown that pPD concentrations of 200 µM and above stimulate significant secretion of CXCL8, a chemokine involved in recruitment of cells expressing CXCR1 and CXCR2. Initial experiments in this study demonstrate that pPD, but not BB, additionally stimulated dendritic cell activation at much lower concentrations (5–50 µM), as measured by increased expression CD40 and MHC class II and stimulation of allogeneic lymphocyte proliferation. Two methods, namely trypan blue dye exclusion and flow cytometry using phosphatidylinositol/annexin V dual staining, were used to confirm that these pPD concentrations were not associated with a significant increase in either apoptotic or necrotic cell death.
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B that results ultimately in further dendritic cell activation (Quezada et al., 2004). Although Bruchhausen et al. (2003) suggest that nuclear factor B may be unimportant for the induction of pPD-mediated dendritic cell migration, these conclusions derive from experiments using high pPD concentrations, and as such, the subtle effects of low pPD concentrations on dendritic cell transcription factor activation remain largely unexplored. Because abnormal CD40 signaling in certain autoimmune diseases is thought to contribute to disease progression (Bour-Jordan et al., 2004; Pollard et al., 2004), the focus of our current research is to determine whether pPD-mediated CD40 signaling is related to susceptibility to pPD sensitization.
Hueber-Becker et al. (2004) recently measured the extent of absorption of pPD-derived material in man as delivered from normal hair dye use. pPD (40%) was applied in combination with the coupler m-aminophenol, which were together mixed with 6% hydrogen peroxide developer before a 30-min application. From this system, 7.0 mg of pPD-equivalent material was delivered systemically. Human skin in vitro was also treated with the same pPD containing hair dye mixture and yielded 10.6-mg equivalents per centimeter squared. It is difficult to relate directly the pPD concentrations associated with dendritic cell activation in our in vitro experiments to actual exposure of dendritic cells in human skin following exposure to pPD as delivered from hair dyes. However, from the above discussion, cutaneous dendritic cells seem likely to be exposed to pPD concentrations that relate directly to our in vitro findings.
Previously, Picardo et al. (1990) demonstrated that pPD degrades within 24 h in buffer at pH 7.4. In the present study, on-line radiometric HPLC and mass spectrometry were used to analyze the fate of [14C]pPD in dendritic cell culture. pPD was converted rapidly to BB (Fig. 5); a minor peak of radioactivity, assigned to the putative [M + 1]+ ion at m/z 137, was the only other pPD derived product detected. Addition of the antioxidant glutathione (1 mM) blocked the formation of BB but not covalent binding of pPD to dendritic cell or serum protein. A glutathione conjugate of pPD was not found. These findings with glutathione suggest that pPD dimerization and BB formation is prevented through the formation of a favorable REDOX cycle between pPD and pPD quinonediimine. As such, cells and/or tissue containing high glutathione levels will be exposed to increased pPD concentrations for a longer duration. A recent report investigating the reactivity of the related compound dimethyl-p-benzoquinoneimine toward amino acids identified a series of often unpredictable adducts, which may relate to the formation of multiple epitopes with protein (Eilstein et al., 2006). Our data show that pPD will associate predominantly with nucleophilic amino acids other than cysteine. Finally, pPD did not bind selectively to cellular or serum protein, which has been observed previously with the types 1 and 2 polarizing chemical allergens dinitrochlorobenzene and trimellitic anhydride (Hopkins et al., 2005).
The addition of glutathione to dendritic cell culture medium provided a simple system to further evaluate the effects of pPD treatment on dendritic cell activation. pPD-mediated increased expression of dendritic cell CD40 was not inhibited with glutathione. Furthermore, in contrast to previous studies that used a higher concentration of glutathione (Iijima et al., 2003), basal and LPS-inducible levels of CD40 expression were not affected. Collectively, these data support a prohapten mechanism of pPD-mediated dendritic cell activation, presumably by covalent binding of pPD quinonediimine to dendritic cell protein. Somewhat surprisingly, the chemical entity presented on MHC molecules to specific T-cell receptors in pPD-mediated contact sensitization is different to that which stimulates dendritic cell maturation. Early studies by Krasteva et al. (1993) suggested that BB, but not pPD or primary oxidation products, stimulate T-cells from allergic patients. More recent studies with cloned T-cells suggest that both pPD and BB actually stimulate T-cells (Sieben et al., 2002). By cloning T-cells from pPD allergic individuals, Sieben et al. (2002) provide evidence to suggest that pPD and BB actually stimulate proliferation of T-cells via two independent mechanisms. pPD was shown to bind directly to MHC and the T-cell receptor in the absence of covalent binding and antigen processing, whereas BB stimulated T-cells via a classical hapten mechanism involving both covalent binding and processing. However, the oxidation of pPD in these in vitro culture systems was not measured; thus, the observed results may be explained by conversion of pPD to BB.
To initiate an immunological reaction, pPD provides two independent signals (Matzinger, 1994; McFadden and Basketter, 2000; Zhang and Tinkle, 2000): firstly, an MHC-restricted antigen, a signal that is dose independent above a threshold; and secondly, a dose-dependent adjuvant-like signal that stimulates dendritic cell activation. An overview of how pPD interacts with dendritic cells is provided in Fig. 6. High concentrations of pPD (or BB) associated with induction of cell death lead to transcriptional activation and increased CD86 expression (Bruchhausen et al., 2003; Hulette et al., 2005). pPD concentrations of 200 µM are associated with the CXCL8 secretion, whereas data presented within indicate that low, nontoxic concentrations of pPD are associated with a specific increase in CD40 and MHC class II expression and allogenic lymphocyte proliferation.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: pPD, p-phenylenediamine; BB, Bandrowski's base; HPLC, high-performance liquid chromatography; LPS, lipopolysaccharide; FITC, fluorescein isothiocyanate; Rt, retention time.
Address correspondence to: Dr. Dean Naisbitt, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, Merseyside, UK. E-mail: dnes{at}liverpool.ac.uk
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