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-Tocopherol Decrease UVB-Induced Lipid Peroxidation and Stress Signaling in Human Lens Epithelial Cells1,2
,3
* Ohio State University Interdisciplinary PhD Program in Nutrition and
Department of Human Nutrition, Ohio State University, Columbus, OH 43210
3To whom correspondence should be addressed. E-mail: failla.3{at}osu.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-tocopherol (-TC) on lipid peroxidation and the mitogen-activated stress signaling pathways in human lens epithelial (HLE) cells following ultraviolet B light (UVB) irradiation. When presented with LUT, ZEA, astaxanthin (AST), and -TC as methyl-ß-cyclodextrin complexes, HLE cells accumulated the lipophiles in a concentration- and time-dependent manner with uptake of LUT exceeding that of ZEA and AST. Pretreatment of cultures with either 2 µmol/L xanthophyll or 10 µmol/L -TC for 4 h before exposure to 300 J/m2 UVB radiation decreased lipid peroxidation by 47–57% compared with UVB-treated control HLE cells. Pretreatment with the xanthophylls and -TC also inhibited UVB-induced activation of c-JUN NH2-terminal kinase (JNK) and p38 by 50–60 and 25–32%, respectively. There was substantial inhibition of UVB-induced JNK and p38 activation for cells containing <0.20 and 
0.30 nmol xanthophylls/mg, respectively, whereas >2.3 nmol -TC/mg protein was required to significantly decrease UVB-induced stress signaling. These data suggest that xanthophylls are more potent than -TC for protecting human lens epithelial cells against UVB insult.
KEY WORDS: • lutein • zeaxanthin • MAPK stress signaling • lipid peroxidation • human lens epithelial cells
Approximately 20 million people in the United States have their vision obstructed by cataracts and 500,000 new cases are diagnosed annually. Current treatment involves surgical extraction, an expensive procedure that is performed over 1.5 million times annually in the United States at an estimated cost of $3.4 billion per year (1). Furthermore, the incidence and costs associated with this disease are certain to increase with the rapidly increasing number of individuals over 65 y of age. Effective strategies aimed at preventing and/or delaying the development of age-related cataract are needed.
Ultraviolet radiation (UVR)4 from sunlight and oxidative stress appear to be the most relevant contributors to age-related cataractogenesis. Results from several epidemiological studies suggest that individuals with high exposure to UVR have an increased risk of cataracts later in life (2,3). A particularly strong association has been observed between cataract development and exposure to radiation wavelengths of 290–320 nm (designated UVB) (4). UVB radiation is thought to contribute to cataract formation by directly damaging DNA (5,6), producing reactive oxygen species (ROS) (7,8), and generating cytotoxic products from actively translating ribosomes (9). In addition to UVB, hydrogen peroxide is chronically present in the aqueous environment surrounding the anterior lens and may contribute to cataract development (10–12). Like all tissues, the lens is equipped with antioxidant defense mechanisms that generally protect against the harmful effects of UV and ROS. Because many of the enzymatic cofactors and chemical constituents necessary for antioxidant activity are obtained only through the diet, adequate nutrition is likely to be important in preventing ROS-induced oxidative damage and maintaining the overall health of the eye (13–15). Indeed, some epidemiological and experimental studies suggest that increased consumption of dietary antioxidants such as vitamin C, vitamin E, zinc, and carotenoids may reduce the incidence or progression of ocular diseases (16–19).
Lutein (LUT) and zeaxanthin (ZEA) are the only dietary carotenoids that are present in the macula region of the retina and the lens (20–22). Dietary supplementation with these xanthophylls increases macula pigment density in human subjects (23,24), primates (25), and quail (26,27). Moreover, it has been reported that chronic intake of high amounts of LUT improved visual acuity and glare sensitivity in several studies with small numbers of subjects with age-related cataracts and macular degeneration (28,29). The above data have served as the impetus for the addition of LUT to a number of multivitamin and mineral preparations and the marketing of numerous LUT and ZEA supplements for healthy vision.
Although considerable efforts are being directed toward defining the potential roles of the xanthophylls in the macula, information about the uptake and possible function of LUT and ZEA in the lens is extremely limited. In addition, the low lenticular concentrations of LUT and ZEA (20,21) challenge the feasibility that these xanthophylls are capable of contributing to the protection of this organ against environmental and endogenous stressors. The present study examined the ability of several xanthophylls to protect cultures of immortalized human lens epithelial (HLE) cells against UVB insult. Epithelial cells comprise the outermost cellular layer of the human lens and are exposed to UV irradiation not filtered by the cornea. UV-induced oxidative damage to these cells is mediated via production of ROS and characterized by alterations in cell growth and morphology, changes in membrane potentials, oxidization of proteins, unscheduled DNA synthesis, DNA strand breakage, and lipid peroxidation (5,6,11).
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Preparation of xanthophylls and -tocopherol:methyl-ß-cyclodextrin (MßCD) complexes.
Stable water soluble complexes of xanthophylls and -tocopherol (-TC) were prepared by complexation with methyl-ß-cyclodextrin as described by Pfitzner et al. (30). The mol/L ratios of MßCD to LUT, ZEA, astaxanthin (AST), and -TC were 12:1, 12:1, 13:1, and 2.5:1, respectively. Stock solutions of complexed xanthophylls and -TC remained stable (99 ± 2%) without isomerization or degradation for as long as 1 y. Prior to experiments, the purity and the concentration of the xanthophylls and -TC complexed with MßCD were verified by HPLC as described below.
Cell culture. The HLE cell line SRA 01–04 was provided by Dr. Venket Reddy (Kellog Eye Institute, University of Michigan). HLE cells were maintained in DMEM supplemented with 100 mL/L heat-inactivated fetal bovine serum (FBS), amphotericin B (0.5 g/L), penicillin-streptomycin (10 mL/L), sodium bicarbonate (44 mmol/L), and HEPES (15 mmol/L) in a humidified atmosphere of 95% air:5% CO2 at 37°C. HLE cells (3.5 x 105 cells) were seeded in 60-mm dishes (Becton–Dickinson Labware) for experiments. Medium was renewed every 2 d and cultures were used for experiments when confluency was 80–95%.
Accumulation of xanthophylls and -tocopherol from CD complexes by HLE cells.
Preconfluent cultures of HLE cells were incubated in serum-free DMEM containing varying concentrations of xanthophylls or -TC as cyclodextrin complexes. After 4 h, spent medium was removed and monolayers were washed once with ice-cold PBS containing 2 g/L albumin and twice with ice-cold PBS. Monolayers were scraped and transferred to 2.0-mL screw-cap conical tubes and centrifuged at 4000 x g for 5 min. Cell pellets were stored under N2 at –80°C. Similarly, preconfluent cultures of HLE cells were incubated in medium containing either 2 µmol/L xanthophyll or 10 µmol/L -TC as cyclodextrin complexes and incubated for varying times to examine cell accumulation of lipophiles with increasing length of exposure. Monolayers were washed, collected, and stored as above.
To assess possible cytotoxicity of MßCD itself and MßCD complexed with xanthophylls and -TC, lactate dehydrogenase (LDH) release was determined as described by Clynes (31). The results are expressed as percentage of the total LDH released to medium, with total LDH activity = released LDH activity + cellular LDH activity.
UVB radiation of HLE cells.
Cultures of HLE were washed twice with warm PBS containing 2 g/L albumin. After buffer was removed, tissue culture dishes without lids were inverted on a support at a fixed distance above a transilluminator (3UV, UVP) and irradiated at 3.0 mW/cm2 for 10 s to achieve a UVB dosage of 300 J/m2 as measured with a calibrated radiometer. Replicate monolayers serving as controls were handled identically except that the UVB light was off. Immediately after treatment, 4 mL DMEM containing 10 mL/L FBS was added to the dish and cultures were returned to the incubator for 30 min. Pilot studies showed that cell viability and morphology were not changed for at least 2 h following exposure to the dose of 300 J/m2.
Lipid peroxidation. HLE cells were washed several times with cold PBS before sonication and centrifugation at 3000 x g at 4°C for 10 min. Lipid peroxidation was assessed in the supernatant as a marker for UV-induced damage. The concentrations of malondialdehyde and 4-hydroxyalkenals were quantified simultaneously by their reaction with N-methyl-2-phenylindole at 45°C. The stable chromophore was measured at 586 nm (Lipid Peroxidation Kit, F-12, Oxford Biochemical Research).
Western blot analysis of MAPK proteins.
Monolayers were harvested for determination of mitogen-activated protein kinase (MAPK) signaling proteins by washing twice with cold PBS before the addition of 60 µL lysis buffer (150 mmol/L NaCl, 1 mmol/L EDTA, 50 mmol/L Tris-HCl, 1% Triton X-100, 0.1% SDS, 50 mmol/L sodium fluoride, 10 mmol/L sodium pyrophosphate, 10 µL protease inhibitor cocktail, and 1.2 mL water). Lysates were sonicated on ice and centrifuged at 20,000 x g for 5 min and the protein concentration of supernatants was measured by bicinchoninic acid method (BCA, Pierce). Protein samples (10 µg) were separated by electrophoresis (180 V, 1 h) and transferred to nitrocellulose and after incubation with appropriate primary and secondary antibodies, protein signals were developed using chemiluminescence detection reagents (Super-Signal, Pierce). Membranes were exposed to Kodak X-OMAT AR film for an appropriate length of time and developed according to the manufacturer’s recommendations. After exposure, films were scanned and band density was quantified using an Image Station 2000R and ID Image Analysis Soflwarc version 3.6 (Eastman Kodak). Density units for each gel band are corrected for variations in loading using the reactivity of total c-JUN NH2-terminal kinase (JNK) and p38.
Extraction and analysis of xanthophylls and -tocopherol.
Cell pellets were resuspended in 500 µL of 35 mmol/L SDS in ethanol containing 4.5 mmol/L butylated hydroxytoluene (BHT) and sonicated for 30 s on ice. Samples were extracted at least twice with 3 mL petroleum-ether:acetone (2:1) containing 4.5 mmol/L BHT. Petroleum-ether layers were combined and dried under a stream of nitrogen. Dried residue was resolubilized in methyl-tert-butyl-ether:methanol (50:50, v:v) for analysis by HPLC.
Xanthophylls and -TC were quantified by HPLC according to Ferruzzi et al. (32) with slight modification described elsewhere (33). Concentrations of LUT and ZEA were calculated from comparison of the area under the curve with known concentrations of the all-trans-isomers of LUT and ZEA standards at retention times of 10.3 and 13.5 min, respectively. The gradient was modified for determination of AST by setting starting mixture of 95:5 A:B with a linear gradient to 40:60 A:B over 20 min. The retention times of cis- and all-trans-AST were 6.8 and 9.3 min, respectively. Isocratic system of reservoir A at a flow rate 0.8 mL/min was used for separation of -tocopherol with a retention time of 11 min. The extinction coefficients, E1cm, 1%, were 2550 for all-trans- and -cis-LUT in ethanol at 450 nm, 2540 for all-trans- and -cis-ZEA in ethanol at 450 nm, 2100 for all-trans- and -cis-AST in hexane at 475 nm, and 71 for -TC in ethanol at 292 nm (34,35).
Statistical analysis. Each experiment was repeated independently at least twice with 2–4 replicate cultures per treatment per experiment. Results are means ± SE. Data were evaluated by one-way ANOVA with Tukey’s post hoc comparisons using Stata 8 statistics program. The level of statistical significance was taken as P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-TC are not cytotoxic.
MßCD complexes of xanthophylls and -tocopherol were stable (mean recovery of 99 ± 3%) after incubation for as long as 8 h in DMEM in cell-free dishes in the incubator. Because cyclodextrins can disrupt cell integrity by removal of cholesterol from the plasma membrane (36), the potential toxicity of MßCD complexed with either 0–4 µmol/L xanthophylls or 0–15 µmol/L -TC was tested; the maximum concentration of MßCD in the test medium containing the highest concentrations of test lipophiles was 52 µmol/L. HLE cells exhibited no evident change in morphology and cell number per well was not altered after incubation with MßCD complexes for as long as 8 h. Furthermore, release of LDH into the medium was similar (P > 0.05) in control cultures (5.9 ± 0.1%) and cultures treated with MßCD complexes (6.5 ± 0.1%). However, the morphology of cells changed from its normal fiber-like appearance (37) to spheres with >50% of cells detaching from the surface within 4 h when the concentrations of complexed LUT and -TC were increased to 8 and 40 µmol/L, respectively. Maximum concentrations of xanthophylls and -TC complexed to MßCD were 2 and 15 µmol/L, respectively, and the period of exposure of cells to the complexes did not exceed 4 h in the experiments described below. These conditions did not affect cell morphology or cell number per culture.
Cell accumulation of xanthophylls and -TC from MßCD complexes.
Cellular content (nmol/mg protein) of xanthophylls increased proportionally as medium concentrations were increased from 1 to 4 µmol/L (Fig. 1A) and with increasing length of exposure (Fig. 1B). However, the amount of each xanthophyll accumulated by HLE cells from the MßCD complex differed with LUT uptake approximately twice that of ZEA (P < 0.001) for each concentration and incubation period tested (Figs. 1A and B). Accumulation of AST was intermediate between LUT and ZEA. Cell concentrations of -TC also increased linearly when monolayers were incubated in medium containing 3 to 15 µmol/L -TC complexed to MßCD and uptake was proportional to length of incubation (Fig. 2).
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-TC decrease UVB-induced lipid peroxidation.
Because lipid peroxidation is a well-established consequence of UVB exposure (7,11), we examined whether preincubation of HLE cells with xanthophylls and -TC affected the extent of lipid peroxidation caused by UVB treatment. Lipid peroxide degradation products (i.e., malonyldialdehyde and 4-hydroxyalkenals) were 214 ± 18 pmol/mg protein in control cultures of HLE cells incubated for 4 h in medium containing 10 mL/L FBS. Incubation of cells with xanthophylls and -TC for 4 h did not (P > 0.05) alter the concentration of lipid peroxidation products (263.6 ± 9.0 pmol/ mg protein) after incubation with 2 µmol/L LUT, ZEA, or AST and 10 µmol/L -TC (265.1 ± 31 pmol/mg protein). UVB exposure (300 J/m2) of control cells or cells pretreated with vacant MßCD increased the concentrations of lipid peroxide degradation products by 525% (Fig. 3). In contrast, incubation of monolayers in medium containing either 2 µmol/L xanthophyll or 10 µmol/L -TC for 4 h before exposure to UVB (P < 0.01) decreased the mean concentrations of malonyldialdehyde and 4-hydroxyalkenals by 52 ± 4% (range of 47–57%) compared to UVB-exposed cultures that were not pretreated (Fig. 3).
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-TC suppress UVB-induced stress signaling in HLE cells.
The MAPK stress signaling pathways are present in lens epithelium (38) and HLE cell line SRA 01–04 (39). To evaluate whether xanthophylls and -TC decrease UVB-induced activation of stress signaling, total and activated (phosphorylated) JNK and p38 were measured in control and pretreated cultures by Western blot. Extracellular signal-related kinase (ERK) was not studied since this protein was activated in the preconfluent cultures and that exposure to UVB exposure did not enhance the degree of activation (39). Phospho-JNK protein (p-p46 and p-p54) was not detected in either control cultures or cultures incubated with 2 µmol/L xanthophyll or 10 µmol/L -TC (Fig. 4A). UVB irradiation markedly activated JNK in cells that had not been exposed to test compounds (Fig. 4A). Preincubation of cells in medium with 2 µmol/L xanthophyll and 10 µmol/L -TC complexed to MßCD suppressed UVB-induced JNK activation by 50–60% (Figs. 4A and B). The decline in JNK activation was similar in cultures pretreated with equimolar concentrations of LUT, ZEA, and AST (Fig. 4B), although the cell content of ZEA was only one half that of LUT (Fig. 1A). Total JNK (nonphosphorylated plus phosphorylated) was similar in all test cultures (data not shown).
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-TC (not shown). Similar to the results for JNK, p38 was phosphorylated when control cultures were exposed to UVB (Fig. 5A). Pretreatment of cultures with LUT, ZEA, AST, and -TC prior to exposure to UVB irradiation reduced (P < 0.05) p38 activation by 34, 14, 30, and 18%, respectively (Fig. 5B).
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-TC at attenuating UVB-induced activation of stress signaling.
HLE cells were incubated in medium containing 0–2 µmol/L LUT or ZEA (concentration of MßCD was constant at 25 µmol/L) for 4 h to vary the intracellular concentrations of the 2 xanthophylls. Cells were then exposed to UVB irradiation and the levels of phospho-JNK and phospho-p38 were determined. The extent of UVB-induced phosphorylation of JNK was inversely proportional to cellular concentrations of the xanthophylls (Fig. 6). Decreases (P < 0.05) in UVB-induced activation of JNK were observed when cell LUT and ZEA concentrations were 0.16 ± 0.02 and 0.15 ± 0.01 nmol/mg cell protein, respectively; these were the cellular concentrations of xanthophylls following incubation in medium with 0.125 µmol/L LUT and 0.25 µmol/L ZEA, respectively. Similarly, UVB-induced activation of p38 decreased (P < 0.05) when cell concentrations of LUT and ZEA were 0.29 and 0.32 nmol/mg protein, respectively; these cell concentrations were achieved after incubation in medium with 0.25 µmol/L LUT and 0.50 µmol/L ZEA for 4 h.
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-TC increased cellular -TC to 5.9 ± 0.11 nmol/mg protein, whereas cells without supplementation had <20 pmol/mg protein -TC. The increased concentration of cell -TC was associated with 51 ± 6 and 32 ± 4% declines in UVB-induced activation of JNK (Fig. 4) and p38 (not shown), respectively. Incubation of monolayers with 5 µmol/L -TC for 4 h increased cell concentration of -TC to 2.3 ± 0.06 nmol/mg protein but failed to decrease UVB-induced phosphorylation of JNK or p38 compared to that in cells not pretreated with -TC (data not shown). |
DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Xanthophylls are extremely hydrophobic compounds, making their delivery to the HLE cells difficult. Whereas a delivery system that is most similar to the physiologic process is preferred, the mechanism for the transfer of xanthophylls and other lipophilic compounds to the nonvascularized lens remains unknown. Carotenoids often are introduced into cell culture models in organic solvents [e.g., ref. (43)] or water-dispersible beadlets (44) and liposomes (45), although problems associated with actual solubility and stability are encountered. Several investigators have reported that liposomes (45), micelles (33,46), and cyclodextrin complexes of carotenoids (30,47) provide effective and nontoxic vehicles for delivery of the pigments to cultured cells and organelles. The complexes remained stable for more than 1 y at –80°C and for 8 h in culture medium. HLE cells accumulated the xanthophylls and -TC in a dose- and time-dependent manner at medium concentrations of the complexes that were not cytotoxic. The efficiency of cell uptake of the xanthophylls from the cyclodextrin particles varied 2-fold with LUT > AST > ZEA. Such differential transfer of carotenoids complexed with cyclodextrin has been observed previously (47). Transfer of ß-carotene, LUT, and canthaxanthin from MBCD to plasma membranes, mitochondria, and microsomes from pig liver was dependent on the specific carotenoid and membrane characteristics. This may be due to differences in binding affinities to the hydrophobic core of the cyclodextrin and perhaps to the distinct orientations of LUT and ZEA within the bilayers (48).
-TC is effective at protecting cells against UV-induced oxidative damage (49,50). Therefore, this compound was selected as an appropriate control for evaluating the photoprotective activities of carotenoids in HLE cells. Carotenoids are lipophilic antioxidants that quench singlet oxygen and scavenge lipid peroxyradicals (40). Induction of carotenoid deficiency in plants by mutation causes photo-oxidative stress characterized by damage to pigments, proteins, lipids, and DNA (51). LUT decreases UVB-induced lipid peroxidation in human skin fibroblasts (45) and ROS generation in murine skin (42). Therefore, it was not surprising that pretreatment of HLE cells with LUT, ZEA, or AST decreased UVB-induced generation of end products of lipid peroxidation by 50%. This protective effect was observed when medium concentration of the xanthophylls was only 20% that of -TC. It also was interesting that while the xanthophylls provided a similar degree of protection against UVB-induced lipid peroxidation, the cellular concentration of ZEA was only one-half that of LUT, suggesting that ZEA is more effective than LUT in protecting lipid membranes against UV-mediated oxidative damage. This observation is supported by Sujak et al. (48), who demonstrated that ZEA protects membranes against lipid peroxidation to a greater extent than LUT.
There is considerable evidence that UV-induced oxidative stress is associated with activation of MAPK and other protein kinase cascades (52). In order to ascertain whether the decline in lipid peroxidation in HLE cells treated with xanthophylls and -TC reflected a more generic reduction in UV-induced photo-oxidative stress, activation of MAPK was assessed. Three major MAPK cascades have been identified, including the ERK 44/42 cascade, which preferentially regulates cell growth and differentiation, and the c-JNK and p38 cascades that mediate cellular stress responses. All 3 of these MAPK signaling pathways are expressed in mammalian lens with activity dominant in the epithelial layer (38). Our data show that UV-induced activation of JNK and p38 in HLE cells is attenuated by pretreatment with LUT, ZEA, AST, and -TC. We next titrated cellular concentrations of LUT and ZEA to determine whether protection occurred at physiologically relevant levels of these compounds. Yeum et al. (20) reported that concentrations of LUT and ZEA, like -TC, were several fold higher in the epithelial/cortical layer than in the nuclear layer of human cataractous lens. The mean quantity of LUT plus ZEA in the outer layer was 77 pmol/g wet wt; -TC content was 5171 pmol/g wet wt. Assuming that the lens is 65% water and that protein represents 60% of the total dry weight (53), the estimated means for LUT/ZEA and -TC are 0.23 and 18.6 nmol/mg protein. We found that UVB-induced activation of JNK was significantly decreased in HLE cells when the concentrations of LUT and ZEA were 0.16 nmol/mg protein. Similarly, UVB-induced activation of p38 was suppressed when the cell content of the xanthophylls was 0.30 nmol/mg protein. It is noteworthy that UVB-induced lipid peroxidation in human skin fibroblasts was attenuated 30–50% when cell LUT content was 0.1–0.9 nmol/mg protein (45). In contrast, UVB-mediated activation of JNK and p38 was observed when cell content of -TC was 5.9 nmol/mg protein, but not 2.3 nmol/mg protein. These data support a photoprotective role for LUT and ZEA in lens epithelial cells. Wrona and associates (54,55) reported that xanthophylls, -TC, and ascorbate act synergistically to protect liposomes and retinal pigmented epithelial cells against oxidative stress. Evaluation of such interactions in the HLE cell line merits attention.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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-tocopherol. FASEB J. 17: A758 (abs.)] and in part at the meeting of Experimental Biology "Translating the Genome" 2004, April 17–21, 2004, Washington, DC [Chitchumroonchokchai, C., Bomser, J. A. & Failla, M. L. (2004) Lutein and zeaxanthin decrease UVB-induced stress signaling in human lens epithelial cells (Abstract No. 367.4)]. 
2 Supported in part by The Ohio State Agriculture Research and Development Center and The Virginia Vivian Scholarship Fund of the OSU Human Ecology College (to C.C.).
4 Abbreviations used: AST, astaxanthin; BHT, butylated hydroxytoluene; ERK, extracellular signal-related kinase; FBS, fetal bovine serum; HLE, human lens epithelial; JNK, c-JUN NH2-terminal kinase; LDH, lactate dehydrogenase; LUT, lutein; MßCD, methyl-ß-cyclodextrin, MAPK, mitogen-activated protein kinase; ROS, reactive oxygen species; -TC, -tocopherol; UVB, ultraviolet B light; UVR, ultraviolet radiation; ZEA, zeaxanthin.
Manuscript received 29 June 2004. Initial review completed 5 August 2004. Revision accepted 30 August 2004.
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