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The Journal of Immunology, 2007, 179, 3604 -3612
Copyright © 2007 by The American Association of Immunologists, Inc.
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The Osmolyte Taurine Protects against Ultraviolet B Radiation-Induced Immunosuppression1

Nicole Rockel*, Charlotte Esser*, Susanne Grether-Beck*, Ulrich Warskulat{dagger}, Ulrich Flögel{ddagger}, Agatha Schwarz§, Thomas Schwarz§, Daniel Yarosh, Dieter Häussinger{dagger} and Jean Krutmann2,*

* Institut für Umweltmedizinische Forschung (IUF) an der Heinrich-Heine-Universität Düsseldorf gGmbH, Düsseldorf, Germany; {dagger} Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; {ddagger} Department of Physiology, Heinrich-Heine-University, Düsseldorf, Germany; § Clinic for Dermatology, Allergology and Venerology, Christian-Albrechts-Universität zu Kiel, Kiel, Germany; and AGI Dermatics, Freeport, NY 11520


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Organic osmolytes, such as taurine, are involved in cell volume homeostasis and cell protection. Epidermal keratinocytes possess an osmolyte strategy, i.e., they take up taurine upon hyperosmotic stress and express the corresponding transporter TAUT. UVB irradiation also triggers taurine uptake and TAUT expression in this cell type. We therefore asked whether taurine plays a role in photoprotection. By using a TAUT-deficient mouse model, lack of taurine in the skin was found to cause a significantly higher sensitivity to UVB-induced immunosuppression. This was not due to an increased generation or decreased repair of UVB-induced DNA photoproducts in the skin of these animals. Instead, decreased skin taurine levels were associated with an increased formation of the soluble immunosuppressive molecule platelet-activating factor (PAF) from the membranes of UVB-irradiated epidermal cells. Blocking PAF activity in taut-deficient mice with a PAF receptor antagonist abrogated their increased sensitivity to UVB-induced immunosuppression. Moreover, taut –/– mice were more sensitive to PAF-mediated immunosuppression than taut +/+ mice. These data suggest that taurine uptake by epidermal cells prevents undue PAF formation, and thereby photoimmunosuppression. Thus, similar to nucleotide excision repair, taurine uptake is critically involved in photoprotection of the skin.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Ultraviolet B (UVB; 290–320 nm) radiation is well known to exert immunosuppressive effects and to inhibit cell-mediated immune responses directed against skin tumors, microorganisms, and contact allergens (1, 2, 3, 4, 5). Contact allergy has been widely used as a model to study the molecular and cellular mechanisms responsible for photoimmunosuppression. Langerhans cells (6) the professional APCs of the epidermis as well as keratinocytes (7), the main epidermal cell type, are involved in the development of contact allergy. Besides reducing the number of Langerhans cells in UVB-exposed murine and human skin areas (6, 8), it appears that UVB radiation-induced immunosuppressive effects are initiated in the nucleus of immunocompetent skin cells through the formation of DNA photoproducts, in particular cyclobutane pyrimidine dimers. Accordingly, UVB radiation-induced immunosuppression was prevented if cyclobutane pyrimidine dimers were removed at increased rates through treatment of irradiated murine or human skin in vivo or skin cells in vitro with liposome-encapsulated DNA repair enzymes (9, 10, 11). In contrast, mice with a defect in nucleotide excision repair showed an increased susceptibility toward UVB radiation-induced immunosuppression (12, 13). Thus, the capacity of skin cells to carry out nucleotide excision repair is important for their protection against UVB radiation-induced immunosuppression.

Recent studies have demonstrated that in addition to nuclear DNA damage, UVB radiation-induced alterations at the level of the cell membrane initiate immunosuppressive effects. In these studies, UVB radiation was found to cause the formation of platelet-activating factor (PAF)3 and PAF-like lipids from keratinocyte cell membranes, which subsequently induced a cascade of keratinocyte-derived, soluble, immunosuppressive factors including IL-10 (14). It is currently not known whether and how skin cells can be protected against UVB radiation-induced immunosuppression that results from this alternative, membrane-dependent pathway.

In this regard we have recently shown that epidermal keratinocytes possess an osmolyte strategy, i.e., upon exposure to hyperosmotic stress keratinocytes accumulate the osmolyte taurine (15). In these studies, taurine uptake was associated with an increased expression of the specific transporter for taurine, i.e., TAUT. Interestingly, increased TAUT expression and taurine uptake were not only observed after hyperosmotic stress, but also upon exposure of keratinocytes to UVB radiation. In nonskin cells, taurine uptake not only serves to regulate cell volume homeostasis but protects various cellular functions and compartments, including the cytoplasmic membrane (16). We now report that taurine uptake is part of the UVB response of skin cells and critically determines their susceptibility toward UVB radiation-induced, PAF-mediated immunosuppression.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Disclosures
 References
 
Mice

Taut-deficient mice were generated by homologous recombination and have a mixed genetic background (C57BL/6 x 129/SvJ) (17). To disrupt the taut locus, an isogenic targeting vector was used to delete the exon 1 of the taut gene. The deletion led to a truncated TAUT protein (from 621 amino acids in the wild type to 450 amino acids) with loss of the transmembrane domain 1 to 3 and part of the extracellular region. Taut –/–, taut +/– and taut +/+ mice were bred in the Institut für Umweltmedizinische Forschung and kept under standard conditions. Male and female animals, 10–20 wks old, were used. All animal experiments were done after obtaining relevant permissions according to German animal protection laws.

1H nuclear magnetic resonance (NMR) spectroscopy of tissue extracts

Animals were sacrificed by CO2 asphyxiation. Freshly shaved back skin from 18-wk-old mice was removed and immediately frozen in liquid nitrogen. Tissues were extracted with perchloric acid, neutralized, and lyophilized. These extracts were redissolved in 0.5 ml of D2O; 512 scans were recorded from a 5-mm 1H/13C dual probe, flip angle of 40°, repetition time 15 s, low power water presaturation, spectral width 5580 Hz, data size 16 K, zero filling to 32 K. Chemical shifts were referenced to (trimethylsilyl)propionic-2,2,3,3d4 acid at 0 ppm. NMR signals were assigned by comparison with literature data (18) and confirmed by spiking the sample with pure compounds. Quantitative evaluation of the spectra was done by using the mixed lorentzian/gaussian deconvolution available under X-WinNMR 2.6 (Bruker). Relative peak areas were obtained by the implemented automatic integration routine. Integrated values were converted to concentrations as previously described (19).

Primary murine epidermal cells (MEC)

Mice, 12–16-wk-old, were sacrificed by asphyxiation with CO2, both ears were cut off and then sterilized with 70% ethanol. In modification of protocols described elsewhere (20, 21): Ear halves were mechanically split and floated on 0.25% trypsin in Ca2+/Mg2+/pyrogen-free PBS on the dermal sides for 2 h at 37°C. Epidermal sheets were collected and filtered through nylon gauze. The resulting single cell suspension was washed in culture medium for MEC (MCDB 153; Biochrom AG) with 2% FCS, 1% L-glutamine, and 10 ng/ml murine epidermal growth factor (PeproTech) and cultured in tissue culture flasks. Cells were split at 85–90% confluency.

UVB exposure

Doses were chosen to be in an effective, nontoxic range according to values derived from the literature or as determined in preliminary experiments. 1) mice: The shaved backs of the animals were exposed to a bank of four Philips UVB TL 20W/12 RS lamps (Eindhoven), which emit UV within the range of 290–340 nm with an emission peak at 313 nm. The energy between 310–315 nm at the target distance of 33 cm was 0.47 mW/cm2 in the middle of the bank. Mice were exposed to UVB or sham exposed four times, on consecutive days; 24 h after the last exposure mice were sensitized with 0.5% dinitrofluorobenzene (DNFB; see below).

2) Cell cultures: 90% confluent MEC were washed twice with prewarmed (37°C) PBS directly before UVB treatment and irradiated through PBS at a distance of 25 cm (0.63 mW/cm2). Immediately after UVB exposure PBS was replaced by prewarmed (37°C) culture medium and the cells were incubated at 37°C for the indicated times. Cells used for PAF measurements were left under PBS at 37°C with 5% CO2 for 10 and 30 min. Control cells were treated identically but were not exposed to UVB radiation.

For PAF inhibition, cells were pretreated with PCA-4248 dissolved in ethanol for 30 min before UVB exposure. Control cultures received a matching amount of ethanol. Preliminary experiments established that this was not toxic to the cells.

Immunofluorescence staining of Langerhans cells

Twenty-four hours after exposing the ears of the animals to UVB (100 mJ/cm2) or after sham irradiation on 4 consecutive days, epidermal sheets were prepared from the ears and stained overnight with rat anti-MHC-II (clone M5/114, B-D Bioscience), detected by Texas red-labeled anti-rat IgG Ab. Sheets were examined microscopically. The number of Langerhans cells was counted from three randomly chosen areas per epidermal sheet. Counting was done independently by two persons in a blinded fashion.

Injection of PCA-4248 and cPAF

One hour before each UVB irradiation mice received an i.p. injection of 125 nmol of PCA-4248 in 100 µl of pyrogen-free saline. Mice treated with cPAF received a daily i.p. injection of 500 pmol of cPAF in 100-µl solvent volume on 4 consecutive days. Control mice and the UVB control mice were injected daily on 4 consecutive days and 1 h before UVB exposure with 100 µl solvent (12.5% DMSO in saline (v/v)) only. Twenty five hours after the last injection mice were sensitized with 0.5% DNFB (see below).

Contact hypersensitivity

Twenty-four hours after the last UVB exposure and 25 h after the last injection, mice were sensitized by painting 75 µl of 0.5% (w/v) DNFB on the irradiated site. DNFB was dissolved in a 5:1 (v/v) mixture of acetone and olive oil. For negative controls, mice were painted with the 5:1 (v/v) mixture of acetone and olive oil only. Five days later the ear thickness of both ears was measured as reference value and 20 µl of 0.3% (w/v) DNFB was applied to both ears. Twenty-four hours after the challenge, ear swelling was measured with a spring-loaded micrometer (Mitutoyo, Japan). Contact hypersensitivity (CHS) was determined as the amount of ear thickness after challenge compared with ear thickness before challenge and is expressed in millimeters x 10–2 (mean ± SD).

PAF measurement

Lipid extraction. MEC were harvested at the indicated time points in ice-cold PBS plus 2% HCl. Pellets were washed and sonicated. Quantification of lipids was done using 500 µg of protein for the Folch extraction (chloroform/methanol (2:1, v/v) + 2% HCl). The lower phase was evaporated under nitrogen, and the lipids dissolved in chloroform/methanol (2:1, v/v).

High performance thin layer chromatography (HPTLC). Samples were separated on silica gel HPTLC plates (20 x 10 cm) Merck 60F 254s, prewashed for 60 min in 2-propanol and dried 20 min at 120°C. Samples were applied to the TLC plates using a CAMAG Linomat IV. For the determination of PAF, samples were separated using an automated multiple development (AMD) procedure on an AMD2 device (CAMAG). This procedure consisted of 20 repeated developments of the chromatogram with a stepwise elution gradient with methanol, n-hexane, water, and chloroform on a CAMAG AMD2 device. Visualization of separated bands was done by postchromatic derivatization after dipping in a manganese chloride solution as previously described (22). After heating the plate for 20 min at 120°C in a temperature controlled oven the plate was dried and scanned on a CAMAG TLC Scanner II with CATS software. Quantification was done by absorption at 550 nm with a plot of peak area versus weight spotted for a series of the standard using a second-order polynomial calibration with PAF-18 as standard.

Determination of UVB-induced cyclobutyl pyrimidine dimer formation

Mice were UVB irradiated on their shaved backs, sacrificed by CO2, and tissue samples from irradiated back skin were taken at indicated time points and immediately frozen in liquid nitrogen. Tissue samples from unirradiated mice served as control. DNA was extracted to high purity using the DNeasy tissue kit (Qiagen); 500 ng of each DNA sample were loaded as triplicates on a southwestern dot blot apparatus. In parallel, UVC-irradiated {lambda} DNA samples (New England Biolabs) were used to generate a standard curve from which cyclobutyl pyrimidine dimer (CPD) incidence was quantified. DNA was transferred to a positively charged nylon membrane (Roche), and CPD detected with an anti-CPD primary Ab (Kamiya Biomedical) and secondary anti-mouse HRP Ab (Amersham). Intensity of Ab-binding was measured with the Kodak Image Station 440CF, and calculated with TotalLab v.2003. In addition, 100 ng of each DNA sample were electrophoresed on a 0.8% ethidium bromide-stained agarose gel and band intensity analyzed with TotalLab v.2003. Gel values were used to normalize the DNA content on the southwestern dot blot. CPD incidence of unirradiated control served as reference for calculating UVB-induced CPD formation.

Real-time PCR

Total RNA from MEC was isolated after exposure to UVB radiation at indicated time points or after sham irradiation as control using a total RNA isolation kit (Macherey-Nagel). Total RNA was reverse transcribed using a first strand cDNA synthesis kit (Invitrogen). Gene expression levels were measured by using QuantiTectSybr Green PCR kit (Qiagen) with the DNA Engine Opticon System (MJ Research) according to manufacturer's instructions. The primers used for PCR were 5'-GACCAGCTGGACAACATACT-3' and 5'-TCAAATGCTCCTTGATTTCT-3' for IL-10, 5'-ATTCCTGGACTGACAGACAC-3' and 5'-GTTCTTCTTAGTGCGTTGCT-3' for ribosomal protein subunit 6 (RPS6), 5'-GTAACCCGTTGAACCCCATT-3' and 5'-CCATCCAATCGGTAGTAGCG-3' for 18S rRNA, and 5'-TGTGTCCGTCGTGGATCTGA-3' and 5'-CCTGCTTCACCACCTTCTTGA-3' for GAPDH. RPS6 and GAPDH served as internal standards.

Statistical analysis

Data were analyzed by unpaired two-tailed Student’s t test using GraphPad Prism software. Differences were considered significant with a p value <0.05. *, p < 0.05; **, p < 0.01; and ***, p < 0.005.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
Reduced taurine levels in the skin of taut-deficient mice

Mice deficient for the functional taurine transporter TAUT have previously been generated by disruption of exon 1 of the taut gene (17). To verify absence of taurine in the skin of these mice, we determined and compared the organic solutes by 1H NMR spectroscopy in homozygous, heterozygous, and wild-type animals. As shown in Fig. 1 and Table I, taurine content was high (9.82 ± 3.86 µmol/g) in taut +/+ mice, amounting to ~24% of all organic solutes measured. In contrast, lack of one or both taut alleles led to reduced taurine content. Taurine was reduced to 6.48 ± 3.07 µmol/g in heterozygous taut +/– animals. With a content of only 0.64 ± 0.16 µmol/g, taurine concentration was reduced by 93% in homozygous taut –/– mice.


Figure 1
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  		FIGURE 1. Skin of taut –/– mice shows strong reduction in taurine level compared with taut +/+ mice. Back skin samples of untreated 18-wk-old mice were isolated and analyzed by 1H NMR spectroscopy as described in Materials and Methods. Representative sections of 1H NMR spectra obtained from perchloric acid extracts of taut –/–, taut +/–, and taut +/+ mouse back skin are shown. Cre, creatine; Lac, lactate; Suc, succinate; Tau, taurine.

 

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  		Table I. Content of organic compounds in skin of taut-proficient and -deficient mice

 
Reduced skin levels of taurine correlated with an increase in the content of other organic compounds in this organ (Fig. 1A, Table I), such as amino acids, organic acids, sugars, or cholines. Quantitatively significant differences between taut +/+ and taut –/– mice were found for acetate, alanine, betaine, carnitine, glutamate, glutamine, glycine, succinate, tyrosine, and valine (Table I). Almost half of the conventional amino acids measured (i.e., 6/13) were up-regulated in the skin of taut –/– mice. In particular, glutamine and glycine levels increased (from 2.2 to 3.8 mM and from 5.7 to 7.3 mM, respectively). Again, these changes correlated with the extent of taurine reduction in heterozygous and homozygous taut-deficient mice. Note that the total osmolarity in the skin remained the same in all genotypes, despite the reduction in taurine.

taut-deficient mice are more susceptible toward UVB-induced immunosuppression

We have previously observed that taurine uptake is increased in epidermal keratinocytes upon exposure to UVB radiation. To assess whether taurine uptake has a role in photoprotection, we next analyzed the susceptibility of taut-deficient mice toward photoimmunosuppression. UVB-induced immunosuppression was studied in vivo by means of contact hypersensitivity (CHS) against a chemical hapten. We exposed taut +/+, taut +/– and taut –/– mice to a low, middle, and high dose of UVB (100 mJ/cm2, 200 mJ/cm2, 400 mJ/cm2). The doses differ from those commonly used on C57BL/6 mice and take into account the mixed genetic background of the taut-deficient mice (23). Animals were sensitized by topical application of DNFB onto the UVB-exposed back skin. The low UVB dose did not induce significant suppression of CHS, neither in taut +/+ (Fig. 2A) nor in taut +/– mice (Fig. 2B), compared with the respective positive control; note though, that taut +/– mice showed a stronger reduction in the ear swelling (~27% compared with positive control) than the taut +/+ (~12%) (Fig. 2D). However, both the middle UVB dose and the high UVB dose induced significant suppression of the ear swelling response in taut +/+ mice as well as in taut +/– mice. In contrast, in taut –/– animals already the lowest UVB dose led to a significant reduction of CHS (42% reduction compared with positive control) (Fig. 2, C and D). Taken together these data demonstrate that taut –/– as compared with taut +/– or taut +/+ mice are more susceptible toward UVB-induced immunosuppression. Increasing the dose eventually led to immunosuppression also in taut +/+ mice. However, the immunosuppressive effects were significantly weaker in the taut +/+ mice compared with the taut –/– mice for the low and middle dose (p < 0.05); at the highest dose the differences were not significant.


Figure 2
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  		FIGURE 2. Taut –/– mice are significantly more susceptible toward UVB-induced immunosuppression than taut +/+ mice. taut +/+ mice (A), taut +/– mice (B), and taut –/– mice (C) were exposed to UVB radiation (100–400 mJ/cm2) before sensitization with a 0.5% DNFB solution. Five days later ear thickness was determined as reference followed by challenging the ears of the mice with a 0.3% DNFB solution. Ear swelling was determined 24 h after challenge. The positive control (pos.) was measured in mice that were sham-irradiated, sensitized, and challenged. Mice representing the negative control (neg.) (background response) were sham-irradiated and ear-challenged without prior sensitization. Results are expressed as means (millimeter x 10–2) plus SEM. Groups consisted of 5 to 9 mice. Data were analyzed by two-tailed Student’s t test. Significant differences verasus respective positive control are marked by asterisks (*, p < 0.05; **, p < 0.01; ***, p < 0.005). A representative experiment is shown; this experiment was performed twice with comparable results. D, UVB-induced suppression of the ear swelling response was calculated as percentage of the respective positive control. Results of suppression of taut +/– and taut –/– mice were analyzed statistically (see above) versus the results of the respective UVB dose of taut +/+ mice.

 
UVB-exposed skin cells of taut knockout mice express higher amounts of IL-10 than skin cells of wild-type mice

IL-10 is an important mediator of immunosuppression and its release by UVB-irradiated keratinocytes has been shown (14, 24). We therefore analyzed IL-10 expression in epidermal cells (MEC) from taut +/+ mice and taut –/– mice by semiquantitative RT-PCR. According to doses used elsewhere for UVB-induced IL-10 triggering in murine keratinocytes (14) we chose 10 and 20 mJ/cm2 UVB for IL-10 expression in MEC. As shown in Fig. 3, A and B, UVB-induced IL-10 mRNA expression in MEC from taut –/– mice stronger than in MEC from taut +/+ mice 2, 4, 8, and 12 h after exposure. At 24 h, IL-10 expression was approximately equal for both genotypes.


Figure 3
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  		FIGURE 3. UVB-exposed skin cells of taut –/– mice express higher amounts of IL-10 than skin cells of taut +/+ mice. MEC of taut –/– (white bars) and taut +/+ mice (black bars) were exposed to either 10 mJ/cm2 UVB (A) or 20 mJ/cm2 UVB (B) at indicated time points. MEC were harvested, total RNA was isolated and analyzed by semiquantitative real-time PCR for IL-10 mRNA expression based on two housekeeping genes. The data are expressed as fold induction compared with sham-irradiated control MEC. Each bar represents the mean + SEM of two independent experiments calculated on both RPS6 and GAPDH expression as housekeeping genes.

 
Note that the kinetics of IL-10 induction also differed for taut –/– and taut +/+ mice. In MEC from taut +/+ the UVB-dependent increase in IL-10 expression was observable only after a lag phase of several hours after irradiation, while in MEC from taut –/– mice IL-10 induction started earlier after irradiation and was stronger (peak of induction: 12 h for taut –/–, and 24 h for taut +/+).

Lack in taurine does not affect UVB radiation-induced CPD formation or repair in mouse skin

DNA damage, predominantly the formation of CPD, is a well-known molecular initiator of UVB-induced immunosuppression (9, 10, 11, 25). Thus, increase of CPD levels in the skin of taut –/– mice compared with taut +/+ mice could explain their higher UVB sensitivity. To test this possibility, all three genotypes were exposed to 100 mJ/cm2 UVB radiation, the UVB dose which had shown the strongest differences in UVB-induced immunosuppression between taut –/– and taut +/+ mice (see Fig. 2). The amount of CPD was determined at 6 and 24 h after UVB exposure. As shown in Fig. 4, CPD were equally abundant in the back skin of all three genotypes, taut +/+, taut +/–, and taut –/– mice at both time points.


Figure 4
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  		FIGURE 4. Lack of taurine does not result in higher UVB radiation-induced CPD formation in mouse skin. Shaved back skin of taut –/–, taut +/–, and taut +/+ mice was exposed to 100 mJ/cm2 UVB radiation. Six and 24 h thereafter tissue samples of irradiated back skin were taken, the DNA was extracted and the content of CPDs was determined. CPD content of DNA isolated from shaved but unirradiated back skin of all three genotypes served as control. A, Representative southwestern dot blots as triplicates of an unirradiated mouse, of a mouse 6 h after UVB exposure, and of a mouse 24 h after UVB irradiation of each genotype. B, Results are expressed as UVB-induced fold CPD induction compared with unirradiated control values of all tested individuals of each genotype. Data are means + SEM. Groups consisted of 3 mice each.

 
Lack in taurine does not affect UVB-radiation-induced reduction of Langerhans cells in mouse skin

UVB radiation reduces the number of Langerhans cells in the exposed skin in mice (6) and humans (8). UVB-reduced Langerhans cells density is associated with an abrogated contact hypersensitvity reaction against haptens such as DNFB (6). Besides this, UVB radiation influences Langerhans cell function in several ways (26, 27, 28, 29). Higher susceptibility toward UVB-induced immunosuppression in taut –/– mice might be explained by a stronger reduction of Langerhans cells after UVB irradiation. Therefore, we determined Langerhans cell density in taut +/+ and taut –/– mice after 100 mJ/cm2 UVB radiation, the same dose we used for determination of UVB-induced CPD formation. Upon UVB irradiation Langerhans cell density of exposed skin was diminished significantly in both genotypes; almost half of the Langerhans cells disappeared from the epidermis (60% for taut +/+; 54% for taut –/–) after irradiation (Fig. 5). Note that control taut –/– mice had a higher LC density (2096 ± 259 LC/mm2) than control taut +/+ mice (1524 ± 188 LC/mm2).


Figure 5
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  		FIGURE 5. Lack in taurine does not affect UVB radiation-induced reduction of Langerhans cells in mouse skin. The ears of the animals were exposed to 100 mJ/cm2 UVB radiation on 4 consecutive days. Control mice were sham irradiated; 24 h after the last exposure the ears were cut off and mechanically split into dorsal and ventral sides. The epidermis was separated from the dermis as described in Materials and Methods. Epidermal sheets were stained with an anti-I-A/I-E mAb and a Texas red-labeled anti-rat secondary IgG Ab. Langerhans cells (Lc) were counted and depicted as Lc/mm2. Lc analysis was done in a blinded fashion by two persons independently.

 
UVB-exposed skin cells of taut-deficient mice release higher amounts of PAF than skin cells of wild-type mice

In addition to nuclear DNA damage, alterations at the level of the cell membrane have recently been shown to initiate UVB-induced immunosuppression. Specifically, release of PAF, which is generated from cell membrane phospholipids in keratinocytes by UVB, triggers a cascade, which involves the release of IL-10 and eventually leads to the suppression of cell-mediated immune responses (14). Because taurine can strongly bind to phospholipids (30) and has membrane-stabilizing properties (31), we next analyzed whether lack in taurine is associated with elevated PAF production in UVB-irradiated primary MEC. PAF is a very potent lipid mediator and shows impact already in pM ranges (14, 32). For direct PAF measurement by HPTLC in MEC supernatant we had to maximize PAF induction. Therefore, we exposed MEC of all three genotypes in vitro to an UVB dose (60 mJ/cm2) known to effectively release PAF in a human epidermal cell line (33). We determined PAF content in total extracts from MEC by HPTLC 10 and 30 min after exposure according to the PAF peak in ionophore-stimulated HaCat keratinocytes (34). Sham-irradiated cells were used as controls (Fig. 6). In MEC from taut +/+ mice UVB exposure did not induce PAF release above background at either time point after irradiation (Fig. 6, black bars). In contrast, MEC from taut –/– mice showed a significant PAF induction of ~1.6-fold 10 min after UVB irradiation, which further increased to ~1.8-fold after 30 min (Fig. 6, white bars). In MEC from the heterozygous taut +/– mice PAF induction by UVB was negligible and not statistically significant after 10 and 30 min (1.1- and 1.3-fold, respectively) (Fig. 6, gray bars). Thus, UVB-induced PAF formation was significantly stronger in the taut –/– mice than in taut +/– or taut +/+ mice (p < 0.05).


Figure 6
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  		FIGURE 6. UVB-exposed skin cells of taut –/– mice release higher amounts of PAF than skin cells of taut +/+ mice. MEC of taut +/+, taut +/–, and taut –/– mice were exposed to 60 mJ/cm2 UVB radiation. 10 and 30 min after UVB exposure lipids were extracted dissolved in chloroform/methanol (2:1, v/v). Control MEC were sham irradiated and subsequently treated identically. Samples were separated on silica gel HPTLC plates, and PAF content was quantified as indicated in Materials and Methods. Results are expressed as UVB-induced fold PAF induction compared with sham-irradiated control MEC. Note that in graph C the ear swelling values of the negative controls were too low to be visible as a bar in the chosen scale of the graph. Data are means + SEM. An asterisk (*) indicates a statistically significant difference analyzed by two-tailed Student’s t test (p < 0.05; two-tailed Student’s t test; n = 6) vs taut +/+ MEC.

 
In taut-deficient mice UVB-induced immunosuppression can be prevented by antagonizing the PAF receptor

To assess whether increased PAF production of UVB-irradiated MEC from taut –/– mice is of functional relevance in vivo for the increased susceptibility of the three genotypes to UVB-induced immunosuppression, we next injected the specific PAF receptor antagonist PCA-4248 i.p. into taut –/–, taut +/–, and taut +/+ mice 1 h before each UVB exposure. The CHS assay was performed as described. Corresponding to the results presented in Fig. 2, irradiation with a UVB dose of 200 mJ/cm2 led to significant immunosuppression in all three genotypes. As expected, the UVB-induced suppression of CHS both in taut +/+ mice (38%, p < 0.05) and taut +/– mice (41%, p < 0.05) was weaker than that in the taut –/– mice (62% p < 0.001) (compare Fig. 7, A–C). Administration of the PAF receptor antagonist PCA-4248 before UVB exposure had no impact on UVB-induced suppression of CHS reaction in taut +/+ mice (Fig. 6A) and in taut +/– mice (Fig. 7B). In striking contrast, injection of the PAF receptor antagonist into taut –/– mice before each UVB irradiation completely abrogated the UVB-induced suppression of CHS (Fig. 6C, p < 0.001), indicating a PAF-dependent suppressive mechanism. We next injected mice with metabolically stable PAF, carbamyl PAF (cPAF) before induction of CHS, to determine whether PAF itself is able to induce immunosuppression in all genotypes. All genotypes became immunosuppressed, indicating that all genotypes are in principle susceptible to PAF-mediated immunosuppression. (Fig. 6, A–C). Note though, that taut –/– mice are more sensitive to cPAF-induced immunosuppression than taut +/+ mice, or the heterozygous taut +/–.


Figure 7
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  		FIGURE 7. In taut –/– mice but not in taut +/+ mice UVB-induced immunosuppression can be blocked by antagonizing the PAF receptor. Taut +/+ mice (A), taut +/– mice (B) and taut –/– mice (C) were exposed to 200 mJ/cm2 UVB on 4 consecutive days. Before each exposure, the mice were injected i.p. with 100 µl of solvent (12.5% DMSO in saline) or 125 nmol of PAF receptor antagonist PCA-4248 (100 µl volume). Alternatively, mice were injected i.p. with 500 pmol of cPAF on 4 consecutive days with sham irradiation. Positive (pos.) and negative (neg.) control mice were injected i.p. with 100 µl solvent only. Twenty four hours after the last treatment, mice were sensitized with DNFB on the back skin. Five days later the ears were challenged with DNFB and the ear swelling response was determined 24 h afterward. Results are expressed as means + SEM. Data were analyzed by two-tailed Student’s t test. Groups consisted of 5 to 6 mice. Significant differences are marked by asterisks (*, p < 0.05 vs respective positive control; **, p < 0.01 versus respective positive control; ***, p < 0.005 versus respective positive control; **, p < 0.01 UVB versus PCA plus UVB).

 
UVB-induced IL-10 induction in MEC can be inhibited by antagonizing the PAF receptor

IL-10 transcript induction by UVB as observed in cultivated keratinocytes (see above) could be inhibited by pretreatment of MEC with the PAF inhibitor PCA-4248. As shown in Table II, UVB-induced IL-10 is decreased by ~50% in taut –/– mice already 4 h after UVB exposure. Although again (see above) the kinetics differ for taut +/+ and taut –/– mice, i.e., in the latter IL-10 induction kinetics is significantly faster and stronger, in both strains the IL-10 induction is sensitive to PAF inhibition with PCA-4248. The effects disappear with time, so that IL-10 transcription decreases again 12 h after treatment.


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  		Table II. UVB-induced IL-10 transcription of MEC can be inhibited by a PAF antagonist

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
Despite its high abundance in tissues, and its manifold functions in cellular homeostasis, little is known until now about the role(s) of the osmolyte taurine in skin cells (15, 35). Prompted by our finding that uptake of taurine and expression of the transporter for taurine, TAUT, are up-regulated by UVB exposure in keratinocytes (15), we studied whether taurine deficiency in the skin of mice influences their susceptibility to UVB-induced immunosuppression. Our results clearly show that taurine (2-aminoethane sulfonic acid) is part of the skin's natural repertoire of defense to prevent photoimmunosuppression.

Like in other tissues (17), the level of taurine is also dramatically decreased in the skin of taut –/– mice. Similar to cardiac muscles, the depletion of taurine was compensated in the skin by an up-regulation of the concentrations of other organic solutes. In contrast, in the skeletal muscles of taut –/– mice, such a compensation was not observed, and this tissue was at the same time functionally compromised, indicating that overall osmolyte balance was critical (36). The reasons for the differential capacity of tissues in taut –/– mice to compensate taurine loss are unknown and warrant further investigation.

The situation in skin differs from that in cardiac muscle. Here, despite the fact that overall osmolarity is also kept through other, compensatory organic solutes, the lack of taurine had adverse physiological consequences, i.e., it resulted in increased susceptibility toward UVB radiation. The osmolyte taurine may have specific properties with regard to prevention of UVB damage, which cannot be provided by other organic solutes. Our findings therefore indicate that the effects found in the skin are due to other functions of taurine, such as antioxidant defense or membrane stabilization (37).

We used contact hypersensitivity, a well-defined immunological (allergic) response initiated by immune cells in the skin, to assess the susceptibility toward UVB-induced immunosuppression in taut-deficient or partially proficient mice. Taut-deficient mice were more susceptible than taut heterozygous or taut proficient mice. However, the effect was dose dependent, i.e., when UVB exposure was high enough, all genotypes became susceptible. Thus, taurine provided partial protection against UVB-induced immunosuppression.

UVB absorption by DNA generates CPDs as the most frequent photoproducts in epidermal cells (38, 39), which subsequently initiate immunosuppression of contact hypersensitivity (11, 40, 41). Taurine has been reported to protect DNA, e.g., from oxidative damage (42). Conceivably, lack of taurine may promote UVB-induced DNA damage in the skin. We tested this possibility, but could not detect any increase in the generation of CPDs, or a decrease in their repair between taut +/+, taut +/–, and taut –/– mice. Similarly, we could not detect a difference between both mouse strains in the UVB-induced depletion of Langerhans cells from skin, which might have accounted for differing sensitivity to immunosuppression.

UVB-induced stress responses have shown to be initiated at the nucleus and in the cell membrane (43). The photoimmunological relevance of the latter has recently been demonstrated by Walterscheid et al., who showed that membrane lipids are altered by UVB-induced reactive oxygen species, causing lipid peroxidation, and oxidative fragmentation of phosphatidylcholine to PAF and PAF-like lipids (14, 32). They demonstrated furthermore, that in a model of systemic immunosuppression, i.e., delayed type hypersensitivity against Candida albicans Ag, PAF-mediated UVB-induced immunosuppression (14).

PAF is a small but very potent signaling molecule. Similar to UVB signaling, PAF receptor activation in epidermal cells stimulates ERK and the p38 MAPK pathways (44, 45), and eventually the synthesis of immunosuppressive soluble factors, including PAF, PGE2 and IL-10 (14, 46, 47). The PAF receptor is expressed in keratinocytes, but not in fibroblasts, and high expression of the PAF receptor in human epidermal cells enhanced UVB-induced apoptosis (33). We found increased production of PAF within minutes after UVB exposure in normal murine epidermal cells, the majority of which are keratinocytes. PAF degradation is very fast in culture, so that we probably have even underestimated the induction. PAF release after UVB has been reported before in a human keratinocyte cell line, KB (33). PAF induction correlated positively and UVB dose-dependently with early IL-10 mRNA expression, suggesting possible involvement of PAF receptor signaling in in vivo photoimmunosuppression of taut –/– mice. When we tested this assumption, we could see that in cultured MEC induction of IL-10 mRNA by UVB can be inhibited by a PAF receptor antagonist, i.e., PAF release can cause IL-10 generation by UVB-irradiated MEC. In vivo, we blocked PAF signaling by injection of a receptor antagonist, and could indeed revert UVB-induced immunosuppression in taut –/– mice. The immunosuppressive capacity of PAF was confirmed by the injection of metabolically stable PAF, which significantly suppressed CHS in all three genotypes. We note that cPAF injection was most effective, i.e., immunosuppressive, in the taut –/– mice, conceivably taut deficiency also affects sensitivity to PAF signaling. Our data corroborate the finding of Walterscheid et al. and extend them to a second model immunological response. The experiment confirmed at the same time, that in contrast to the taut –/– mice, for taut +/+ and taut +/– mice PAF release is not a major mechanism of their UVB-induced immunosuppressive response in CHS. Apparently, other mechanisms responsible for UVB-induced immunosuppression are more pronounced in these mice, such as DNA damage (11), the isomerization of urocanic acid (48), reactive oxygen species (49), or a combination of them. Interestingly, hypersensitivity toward photoimmunosuppression was overcome in the case of the taut –/– mice by cPAF, despite the fact that the mice have DNA damage (see Fig. 3). Thus, for these mice the DNA damage appears less important in mediation of immunosuppression than for the wild-type mice.

How can taurine prevent the abnormal formation and release of PAF, which is caused by the UVB-induced hydrolysis of membrane lipids? First, direct stabilizing interactions of taurine with membrane lipids are possible. Huxtable described ion pairing between taurine and the head groups of neutral membrane lipids like phosphatidylethanolamine and phosphatidylcholine (30, 50). Alternatively, taurine can modulate the membrane composition. Taurine-enriched nutrition lowered the level of phosphatidycholine and adjusted abnormal lipid-protein ratios in the liver of guinea pigs. Another possibility is the modulation of calcium availability by taurine, which has been described before (37), and which could counteract UVB-mediated adverse effects on Ca2+ homeostasis. Further studies will be needed to clarify the extent of a possible change in calcium homeostasis and its possible contribution to UVB-induced immunosuppression in taut-deficient mice.

Cell swelling stretches the cell membrane, thereby influencing stretch-sensitive channels and in turn altering cell membrane potential (51). Moreover, the cellular hydration status affects metabolic pathways, intracellular signaling pathways, as well as gene expression (for review, see Ref.16). In our study, however, the osmoregulatory actions of taurine appeared to be less important, as we found a compensation of taurine absence by other solutes, providing constant osmolarity in the skin.

UVB damage affects many cellular compartments and components. Here we identified taurine as a novel endogenous factor in protection against photoimmunosuppression. This novel UVB defense mechanism complements the well-studied mechanisms protecting DNA (e.g., nucleotide excision repair), the oxidative balance, and pigmentation. It is tempting to speculate that topical application of taurine or a taurine-enriched diet might be effective in sun protection. It is currently not known whether possible genetic polymorphisms of taut in humans relate to sun sensitivity and increased photo damage initiating skin cancers. A number of SNPs are described for the taut gene (http://www.ncbi.nlm.nih.gov), but nothing is known about their clinical relevance.

In summary, our results clearly suggest a protective role for taurine against UVB-induced immunosuppression. Taurine protects from UVB at the level of the cell membrane. In particular, we demonstrated that the UVB-induced generation of signaling lipids such as PAF is controlled by taurine.


   Acknowledgments
 
We thank Swantje Steinwachs, Alla Velgach, Daniela Brammertz, and Heidemarie Brenden for expert technical assistance. We are grateful to Dr. Irmgard Förster for critical reading of the manuscript.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported through the Deutsche Forschungsgemeinschaft (SFB 503 "Molecular and cellular mediators of exogenous noxes" and SFB 575 "Experimental Hepatology"), the Bundesministerium für Umwelt, and the BMFZ at the Heinrich-Heine University of Düsseldorf. Back

2 Address correspondence and reprint requests to Prof. Dr. Jean Krutmann, Institut für Umweltmedizinische Forschung (IUF) gGmbH, Auf’m Hennekamp 50, Düsseldorf, Germany. E-mail address: krutmann{at}rz.uni-duesseldorf.de Back

3 Abbreviations used in this paper: PAF, platelet-activating factor; 1H NMR spectroscopy, proton nuclear magnetic resonance spectroscopy; CHS, contact hypersensitivity; CPD, cyclobutyl pyrimidine dimers; DNFB, dinitrofluorobenzene; MEC, primary murine epidermal cells; AMD, automated multiple development; RPS, ribosomal protein subunit. Back

Received for publication August 17, 2006. Accepted for publication July 9, 2007.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
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