Materials and methods

Cell culture

Primary skin fibroblasts used were XP-A (XP12BE-GM05509), XP-C (XP23BE-AG10032; XP30BE- KR05792; and XP21BE-GM09943), XP-D (XP29BE-GM11613) and normal (NHFB) and SV40-transformed XP-A [XP2OS (SV40)-GM04312], complemented XP-A (XP2OS-PCAH19WS-GM15876) (^{Levy et al, 1995}), XP-D [XP6BE (SV40)-GM08207] and complemented XP-D (XP6BE-ER2-9-GM15877) (^{Gözükara et al, 1994}) cells. The XP cells were obtained from the Human Genetic Mutant Cell Repository, Camden, NJ. Cells were maintained in Dulbecco's modified Eagle's medium (DMEM) with 20% fetal bovine serum (FBS). Before confluence, they were subcultured with 0.05% trypsin-0.53 mM ethylenediamine tetraacetic acid solution, followed by washing using phosphate-buffered saline (PBS) with 10% FBS. The fibroblasts of fourth-fifth passages were plated on a 10 cm culture dish at a cell density of 4 10³ per cm² and cultured for 48 h before irradiation with UVB or lipopolysaccharide (LPS) treatment.

UVB irradiation and MTT assay

A polychromatic UVB light source with four fluorescent bulbs (FS20T12-UVB, National Biological Corporation) was used. The irradiation was 0.36 mW per cm² at a target distance of 15 cm. Immediately before irradiation, cells were washed with PBS and irradiated in the presence of 0.5 ml PBS without the plastic dish lid. Exposure times were less than 1 min and the temperature increase during irradiation was less than 0.5°C. Controls were treated in the same manner but the UV source was not turned on. Immediately after irradiation, cells were cultured with DMEM for 6, 12, and 24 h. Previous studies have demonstrated that doses of UVB in the range of 100–200 mJ per cm² are optimal for cytokine induction (^{Fujisawa et al, 1997}). This dose was very toxic for XP fibroblasts, however. In order to decide the optimal UVB dose, an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay was performed 24 h after 50 mJ per cm² of UVB irradiation as described previously with some modification (^{Duffy et al, 1987}). Briefly cells were washed twice with PBS 24 h after irradiation and then incubated in 0.15% MTT/complete medium for 3 h at 37°C. Cells were lyzed and reacted with acidified isopropanol for 10 min at room temperature and then 100 l of solution was transferred into a 96-well microtest plate. Samples were analyzed by means of a microplate reader (Bio-Rad) with 656 nm filter. Short-term cell survival rates were measured as the rates of the irradiated samples divided by the rate of the control cells without irradiation.

LPS treatment and MTT assay

For nonspecific cytosine induction, cells were treated with 100 ng per ml LPS, an endotoxin. Immediately before treatment, cells were washed with PBS and incubated with DMEM containing 20% FBS and 10 ng per ml LPS. Controls were treated in a similar manner but no LPS was added. Cells were cultured for a 24 h period and then the MTT assay was performed, as described above.

RNA extraction and reverse transcription

RNA was obtained as previously described (^{Kondo et al, 1994b}). Briefly, cells were lyzed in RNA Stat-60TM (Tel-Test "B", Friendswood, TX). Total RNA was extracted according to the manufacturer's instructions. Two micrograms of total RNA was dissolved in 10 l of water containing 10 U of RNazein (Pharmacia, Lavel, Quebec, Canada) and 1 g of oligo-dT primers (Pharmacia), heated to 65°C for 5 min, and then chilled on ice. This solution was mixed with reverse transcriptase buffer [final concentration, 60 mM KCl, 50 mM Tris (pH 8.3), 3 mM MgCl₂] (Gibco BRL), 10 mM dithiothreitol (DTT) (Gibco BRL), 10 mM of each dNTP (Boehringer Mannheim, Dorval, Canada), and 200 U of Moloney murine leukemia virus reverse transcriptase (Gibco BRL) to a total volume of 20 l. After 1 h incubation at 37°C, the reaction was stopped by heating at 95°C for 5 min.

Polymerase chain reaction (PCR)

PCR were performed as described previously (^{Kondo et al, 1993;1994a}). Primer sets for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), IL-1, IL-6, and IL-8 were synthesized at Dalton Chemical Laboratories (Toronto, Ontario, Canada). Specific cDNAs obtained from the reverse transcriptase mixture were amplified in a total volume of 10 l containing PCR buffer [final concentration, 50 mM KCl, 10 mM Tris-HCl (pH 8.3), 1.5 mM MgCl₂] (Pharmacia), 2 M each primer, and 0.25 U of Taq DNA polymerase (Pharmacia). The mixture was overlaid with 15 l of mineral oil. PCR cycles were performed in a Perkin-Elmer Cetus Thermal Cycler 480 (Perkin-Elmer, Norwalk, CT) with denaturation for 1 min at 95°C, annealing at 60°C for 45 s, and extension for 30 s at 72°C. Optimal PCR cycle numbers were determined for each gene product.

Analysis of PCR products

An aliquot (10 l) of each PCR product was loaded onto 1.5% agarose gels containing ethidium bromide and electrophoresed for 10–20 min at 100 V. The gels were photographed under UV light. Negative films were scanned by means of a laser densitometer (KLB 2222-020, Ultrascan XL, Pharmacia) for semiquantification of c-DNA. Densitometric values of each cytokine were normalized to that of GAPDH.

Statistical analysis

All data were expressed as mean standard error of the mean (SEM). The statistical significance of differences between the means was determined by applying the Student's t test (two-tailed). A difference was considered to be statistically significant for p < 0.05.

Results

Reduced survival of XP cells compared to normal cells

As XP cells are hypersensitive to UVB, we wanted to determine a dose of UVB that would stimulate XP cells but not be so toxic that mRNA would be degraded. We found that with 50 mJ per cm² of UVB survival of NHFB was 76% whereas survival of the XP lines was 50%-68% as measured by the MTT assay (data not shown). This dose was utilized for all subsequent experiments.

Markedly reduced UVB upregulation of IL-1 in XP cells

XP-A, XP-D, and NHFB fibroblasts were cultured and irradiated with UVB, and mRNA levels of IL-1 were examined by semiquantiative reverse transcriptase PCR. Whereas IL-1 mRNA was induced in NHFB 24 h after UVB irradiation, the induction of IL-1 mRNA in XP-A, XP-C, and XP-D fibroblasts was decreased significantly to almost undetectable levels (Figure 1, Figure 2, upper panel).

Figure 1.

Impaired cytokine mRNA expression induced by UVB irradiation in XP fibroblasts. Cultured XP fibroblasts and NHFB were irradiated with 50 mJ per cm² of UVB, total RNA was extracted 24 h later, and cytokine mRNA expression level was examined by means of reverse transcriptase PCR. IL-1 and IL-6 mRNA expression but not IL-8 mRNA expression was impaired in all XP fibroblasts compared to NHFB.

Full figure and legend (35K)

Figure 2.

Cytokine mRNA expression induced by UVB irradiation in XP fibroblasts. Fibroblasts from XP patients and NHFB were irradiated with 50 mJ per cm² of UVB and mRNA was analyzed by reverse transcriptase PCR. Semiquantification was performed by comparing densitometer levels of each cytokine to that of GAPDH and the results are indicated as relative mRNA expression. Upper panel: Relative IL-1 mRNA expression induced by UVB irradiation was significantly lower with all the XP cells than with the NHFB. Middle panel: Impaired IL-6 mRNA expression induced by UVB irradiation in XP fibroblasts. The XP-C cells showed greater induction than the XP-A and XP-D cells. Lower panel: Normal relative IL-8 mRNA expression induced by UVB irradiation in XP fibroblasts.

Full figure and legend (43K)

Impaired UVB-induced IL-6 induction of XP fibroblasts

The constitutive level of IL-6 mRNA expression in all five XP fibroblast cultures was significantly lower than that of NHFB. After UVB irradiation IL-6 mRNA was minimally upregulated in the XP-A and XP-D fibroblasts. Although IL-6 mRNA induction of XP-C fibroblasts increased after UVB irradiation, the mRNA level was much lower than that of NHFB (Figure 1, Figure 2, middle panel).

Intact UVB-induced IL-8 induction of XP fibroblasts

IL-8 mRNA expression in NHFB and XP fibroblasts was upregulated after UVB irradiation. The five XP fibroblasts lines did not demonstrate any significant difference from the normal cells (Figure 1, Figure 2, lower panel).

Cytokine induction in complemented XP-A and XP-D cells

In order to provide additional evidence for the action of DNA repair in cytokine induction, stably complemented XP-A and XP-D fibroblasts containing the respective wildtype human repair enzymes were treated with UVB irradiation. There was a substantial increase in induction of IL-1 mRNA after UVB in the complemented XP-A and XP-D cells in comparison to the repair-deficient cells. The level of IL-1 mRNA in the complemented XP-A and XP-D cells was similar to that in the normal cells (Figure 3, upper left panel). In addition, the relative expression of IL-6 mRNA induction after UVB was significantly elevated in the complemented XP-A and XP-D cells in comparison to the repair-deficient cells (Figure 3, middle left panel). The relative expression of IL-8 mRNA was not significantly different from the normal cells for the four XP cell lines (Figure 3, lower left panel).

Figure 3.

Cytokine mRNA expression induced by 50 mJ per cm² UVB and 100 ng per ml LPS in complemented XP-A and XP-D fibroblasts. Left column, solid bars, 50 mJ per cm² UVB; right column, striped bars, 100 ng per ml LPS. Upper panels: Relative IL-1 mRNA expression induced by UVB irradiation was increased in the complemented XP-A and XP-D cells compared to the XP-A and XP-D cell lines. LPS induced IL-1 mRNA expression in all five cell lines. Middle panels: Relative IL-6 mRNA expression induced by UVB irradiation was significantly increased in the complemented XP-A and XP-D cells compared to the XP-A and XP-D cell lines (nt, not tested). LPS induced IL-6 mRNA expression in all four cell lines tested. Lower panels: Relative IL-8 mRNA expression induced by UVB irradiation was not significantly different in the complemented XP-A and XP-D cells compared to the XP-A and XP-D cell lines. LPS induced IL-8 mRNA expression in all five cell lines tested. (NL, NHFB; A, XP-A cells; A-C, complemented XP-A cells; D, XP-D cells; D-C, complemented XP-D cells. Bars indicate mean SEM for two to seven replicates for each cell line.)

Full figure and legend (59K)

To exclude the possibility that XP fibroblasts have a general impairment in their ability to induce IL-1, IL-6, or IL-8, XP and normal fibroblasts were treated with a nonspecific cytokine stimulator (100 ng per ml LPS). The relative level of IL-1 mRNA was observed to be induced equally in the XP and NHFB cells (Figure 3, upper right panel). The relative level of IL-6 mRNA was equally increased in the four XP cell lines (Figure 3, middle right panel). The relative level of IL-8 was increased in the four XP and normal cells (Figure 3, lower right panel). Thus the repair-deficient XP cells are capable of expressing IL-1, IL-6, and IL-8 cytokine mRNAs.

Discussion

XP

XP is a rare, autosomal recessive disease in which patients develop excessive solar damage at an early age and have a 1000-fold increased risk of developing cutaneous neoplasms (^{Kraemer et al, 1987;1994}). The mechanism of carcinogenesis in XP patients has been thought to due to their reduced capacity to repair UV-induced DNA damage by NER. Based on cell fusion studies and molecular analysis of cloned DNA repair genes, XP is classified into seven DNA NER complementation groups (^{Van Steeg and Kraemer, 1999}).

Immune modulation by UVB

Although UV radiation has a direct carcinogenic effect by inducing DNA damage, it has become clear that exposure to UVB can cause profound immunologic alterations. Acute UVB irradiation induced impaired contact hypersensitivity to cutaneous antigens and induced antigen-specific tolerance (^{Ullrich et al, 1986;Yoshikawa et al, 1990}). DNA and urocanic acid, which are two candidate photoreceptors, initiate a cascade of events mediated through cytokines that finally lead to immunosuppression (^{Ross et al, 1986}).

Numerous studies have demonstrated that UVB irradiation can alter secretion of cytokines by epidermal keratinocytes and dermal fibroblasts (^{Kock et al, 1990;Kondo et al, 1993;Enk et al, 1995;Chung et al, 1996;Fujisawa et al, 1997}). The UVB-induced alterations in cytokine production have been implicated in UVB immunosuppression and in UVB-induced carcinogenesis (^{Gensler et al, 1995;Eberlein-König et al, 1998}). Cytokines are also thought to play a role in UVB-induced carcinogenesis by altering either antigen presentation or the balance between Th1 and Th2 (^{Schirrmacher et al, 1998}). Most research into the mechanism of UVB induction of cytokines has focused on several transcription factors and proteins such as AP-1, NFB, NF-IL6, and heat shock proteins but the role of DNA NER on the induction of these molecules is unknown (^{Shimizu et al, 1990;Mastronarde et al, 1996;Roger et al, 1998;Todryk et al, 1999})

Immune response in XP

A number of reports indicate impaired immune response in XP patients including a decreased ratio of helper/suppressor T cells, impaired mitogen response of lymphocytes, impaired production of IFN- in lymphocytes, and reduced normal killer activity in the absence of UVB stimulation (^{Agarwal et al, 1977;Wysenbeek et al, 1986;Anstey et al, 1991;Gaspari et al, 1993}). UVB irradiation was reported to induce delayed recovery of Langerhans cells and enhanced inhibition of ICAM-1 expression in XP (^{Dupuy and Lafforet, 1974;Morison et al, 1985;Wysenbeek et al, 1986;Anstey et al, 1991;Mariani et al, 1992;Gaspari et al, 1993}). Recently this impaired immune response was confirmed with an animal model of contact hypersensitivity that utilized XPA gene deficient mice (^{Miyauchi-Hashimoto et al, 1996}).

In this study, we found reduced expression of the cytokine IL-6 in fibroblasts from XP patients after UVB radiation. IL-6 is reported to have a protective effect against skin cancer. For example, local secretion of IL-6 inhibits tumor growth by recruiting and proliferating tumor-associated macrophages in situ and is thought to protect the common nevi from progression to malignant melanoma (^{Dougherty et al, 1994;Ahmed et al, 1995}). As the amount of UVB that penetrates to dermal fibroblasts is much less than that received by epidermal cells in intact skin, the results of our study should be considered as a model for other epidermal immune cells. If these cells respond in the same manner as the dermal fibroblasts, then impaired cytokine mRNA expression may contribute to the high incidence of skin cancer in XP patients.

In order to exclude the possibility that XP cells are generally impaired in their ability to release cytokines, cells were treated with an endotoxin, LPS. The fact that there is no downregulation of IL-1 or IL-6 following LPS treatment in all cell lines Figure 3 demonstrates that both XP-A and XP-D cells are capable of expressing IL-1 and IL-6 mRNA.

UVB-induced cytokine transcription and DNA repair

Several cell biologic activities are known to be dependent on NER. The expression of ICAM-1 and cell cycle regulation by p53 are thought to regulated in a DNA-repair-dependent manner (^{Yamaizumi and Sugano, 1994;Ljungman and Zhang, 1996;Ahrens et al, 1997;Dumaz et al, 1997;Washio et al, 1999}). The effect of UV on NF-B activation appears to have a rapid DNA-damage-independent phase and later a DNA-dependent phase (^{Bender et al, 1998}) The late phase activation is observed in XP-A cells at a lower dose of UVC than in normal cells. Further, IL-1 transcription stimulation by UVC was barely detectable in XP-A cells (^{Bender et al, 1998}). In contrast, the response of exonuclease-1, which plays an important role for DNA replication, to UVB irradiation is thought to be DNA repair independent (^{Qiu et al, 1998}). The report by^{Kulms et al (2000)} provides evidence that UVB induction of IL-6 in HeLa cells is mediated by membrane events.

Our results indicate a role for NER in mRNA expression of some cytokines. Expression of IL-1 and IL-6 is dependent on NER as UVB induction of these cytokines is nearly absent or markedly diminished in DNA-repair-deficient fibroblasts (Figure 2, upper and middle panels) and is restored by correction of the DNA repair defect by stable introduction of the wildtype human DNA repair gene into XP-A and XP-D cells (Figure 3, upper and middle left panels).

The exact role of NER in stimulating transcription of some cytokines remains unknown. These cytokines might be stimulated by removing photoproducts that block transcription and replication in a manner analogous to that reported in p53 induction (^{Hupp et al, 1995;Ljungman et al, 1996;Blattner et al, 1999}). Alternatively, the signal may be the presence of nicks generated in DNA in the course of removing photoproducts from transcriptionally active genes. The nicks may in turn stimulate other responses that ultimately elevate cytokine expression.^{Kulms et al (2000)} reported that removal of DNA damage by photoreactivating enzyme plus UVA light did not alter the release of IL-6 in HeLa cells exposed to UVB. This enzyme directly reverses cyclobutane dimers in DNA without creating nicks and does not utilize the NER system that normally acts on this damage in repair-proficient cells. This observation suggests that the stimulating factor for UVB-induced IL-6 induction is not the presence of photoproducts in DNA. It is possible that NER action on nondimer photoproducts that remain after treatment with photoreactivating enzyme provides a signal for IL-6 induction.

Our results demonstrated normal upregulation of IL-8 after UVB irradiation in XP patients but abnormal reactions of IL-1 and IL-6 suggesting that these genes are regulated differently with UVB. Thus IL-1 and IL-6 appear to be induced through a mechanism that involves DNA NER whereas IL-8 induction is independent of DNA excision repair. Hence induction of IL-1 and IL-6 may involve DNA damage whereas IL-8 induction may involve other targets such as the cell membrane. These results also imply that IL-1 and IL-6 may be more important than IL-8 for the induction of skin cancer in XP patients.

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