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ABSTRACT: The role of cytokines and arachidonic acid metabolites in the regulation of IgE production in healthy persons and in atopic dermatitis patients with elevated IgE levels was studied. Interleukin-4 (IL-4) induced IgE production in peripheral blood mononuclear cells (PBMCs) of all donors, and no significant difference was found between the amounts of IgE produced by healthy persons and atopic dermatitis patients. Similarly, recombinant interferon (IFN)-α and IFN-γ, as well as IL-2, inhibited IL-4-induced IgE production to a similar extent in both study groups. To evaluate the role of arachidonic acid (AA) metabolites in the regulation of IgE production, we added indomethacin, an inhibitor of the cyclooxygenase pathway, or nordihydroguaiaretic acid (NDGA), an inhibitor of the lipoxygenase pathway, to IL-4-treated cultures. Both indomethacin and NDGA strongly inhibited IL-4-induced IgE production. They also inhibited IL-4-induced IgG4 synthesis. No significant difference in the amount of inhibition was found between the two study groups. We were unable to restore the NDGA-induced inhibition of IgE-production by adding leukotrienes B4, C4, D4, or 5-HETE to the NDGA-treated cultures. PGE2 also failed to restore the indomethacin-mediated inhibitory effect. Consequently, NDGA- and indomethacin-mediated inhibitory effects do not appear to be mediated by any single factor studied. Collectively, our results show IFNs and IL-2 to be similar in effect in the modulation of IL-4-induced IgE synthesis in healthy and atopic persons. In addition, our results show the importance of AA metabolites in the regulation of IgE and IgG4 synthesis in normal persons as well as in atopic dermatitis patients.
Allergy 04/2007; 48(3):189 - 195. · 6.27 Impact Factor
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Duodecim; lääketieteellinen aikakauskirja 02/2001; 117(6):557-60.
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ABSTRACT: A deamination product of histidine, urocanic acid, accumulates in the skin of mammals as trans-urocanic acid. Ultraviolet (UV) irradition converts it to the cis-isomer that is an important mediator in UV-induced immunosuppression. We have recently shown that urocanic acid interferes with the agonist binding to GABA(A) receptors. We now report that the effects of urocanic acid on binding of a convulsant ligand (t-butylbicyclo[35S]phosphorothionate) to GABA(A) receptors in brain membrane homogenates are dependent on pH of the incubation medium, the agonistic actions being enhanced at the normal pH of the skin (5.5). Using Xenopus laevis oocytes expressing recombinant rat alpha1beta1gamma2S GABA(A) receptors, the low pH potentiated the direct agonistic action of trans-urocanic acid under two-electrode voltage-clamp, whereas cis-urocanic acid retained its low efficacy both at pH 5.5 and 7.4. The results thus indicate clear differences between urocanic acid isomers in functional activity at one putative receptor site of immunosuppression, the GABA(A) receptor, the presence of which in the skin remains to be demonstrated.
European Journal of Pharmacology 08/2000; 400(1):11-7. · 2.52 Impact Factor
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ABSTRACT: The aim of this study was to investigate whether patients with basal-cell carcinoma (BCC) of the skin have an increased risk of developing other cancers. A total of 71,924 patients diagnosed with BCC between 1953 and 1995 were identified from the Finnish Cancer Registry. They were followed up for subsequent primary cancers from the date of the first BCC diagnosis to the end of 1995. Standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated based on national rates. Altogether 11,042 subsequent primary cancers occurred among the study cohort during 625,000 person-years of follow-up. Risk increases were observed for non-melanoma skin cancer (SIR 3.79, 95% CI 3.59-4.00) and skin melanoma (SIR 2.34, 95% CI 2.08-2.61). The five other primary sites presenting the highest SIRs were salivary glands (SIR 3.30), lip (2. 19), small intestine (1.85), nose (1.73) and pharynx (1.71). Patients who were less than 40 years of age at the time of BCC diagnosis had a significantly higher relative risk for a subsequent new cancer than the older patients (ratio of the SIRs 1.29, 95% CI 1. 10-1.51). Time since BCC diagnosis did not materially influence the overall relative risk of subsequent cancers. Part of the increase in the risk of skin cancer is likely to be due to enhanced diagnostic activity after an initial diagnosis of BCC. However, the increases in the risk of several non-cutaneous cancers suggest a generalized carcinogenic role of some factors in the BCC pathogenic pathways.
International Journal of Cancer 08/2000; 87(2):283-8. · 5.44 Impact Factor
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ABSTRACT: Ultraviolet-A radiation (UVA) of the oral mucosa after photosensitization with either systemic methoxsalen (8-MOP) or topical trioxsalen (TMP), i.e. mouth-PUVA, has been reported to be successful in the treatment of oral lichenoid lesions. In the case of PUVA treatment of skin disorders, local immune suppressive effects have been demonstrated, and the antigen presenting epithelial Langerhans cells (LCs) have been shown to be especially sensitive to ultraviolet treatments. Our aim was to compare the photobiological effects of PUVA in oral mucous membrane (OMM) using topical TMP or systemic 8-MOP photosensitization.
Rat OMM photosensitized with topical TMP or systemic 8-MOP was treated with PUVA using UVA doses of 1-8 J/cm2. The LCs were demonstrated in epithelial sheets of the treated OMM with ATPase staining.
Both treatments caused a sim ilar, dose-dependent depletion of ATPase-positive LCs, with a maximal depletion of 80% or 73% with 8 J/cm2 at 2 days after irradiation as photosensitized with TMP or 8-MOP, respectively. This contrasts with earlier published findings in human skin, where topical TMP is an order of magnitude greater a sensitizer than 8-MOP, and PUVA-induced depletion of LCs occurs maximally 5 days after irradiation.
The depletion of LCs of rat OMM after PUVA treatment is greater using topical TMP compared to systemic 8-MOP, but the difference is significantly smaller than reported earlier in human skin.
Photodermatology Photoimmunology and Photomedicine 07/2000; 16(3):129-33. · 1.30 Impact Factor
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ABSTRACT: Long-term oral 8-methoxypsoralen (8-MOP) and UVA (PUVA) therapy increases the risk of nonmelanoma skin cancer and possibly also of cutaneous malignant melanoma. Topical application of 8-MOP PUVA induces malignant tumors in rodent skin, but little is known about its carcinogenicity in human skin.
Our purpose was to investigate the carcinogenicity of 8-MOP bath PUVA in humans.
This was a cohort study of 158 patients with psoriasis, for whom 8-MOP bath PUVA had been initiated during 1979 to 1992. The average number of 8-MOP bath PUVA treatments was 36 (range, 6 to 204) and the mean cumulative UVA dose was 92 J/cm2 (range, 3 to 884 J/cm2) by the end of 1995. The patients were not treated with any other forms of PUVA. Cancer incidence subsequent to 8-MOP bath PUVA up to the end of 1995 was determined by linking the cohort with the records of the Finnish Cancer Registry. The standardized incidence ratios (SIR) were calculated for skin cancer and some common internal cancers, using the expected numbers of cases based on the regional cancer incidence rates.
There was one case of basal cell carcinoma, but no cases of other types of skin cancer. A total of 6 noncutaneous cancers were observed (SIR, 1.3; 95% confidence interval, 0.5 to 2.8).
No association between cutaneous cancer and 8-MOP bath PUVA was found, but the statistical power of this study alone is not adequate to warrant definite conclusions. The results can be used in a meta-analysis as soon as other studies on the carcinogenicity of 8-MOP bath PUVA are published.
Journal of the American Academy of Dermatology 06/1999; 40(5 Pt 1):694-6. · 3.99 Impact Factor
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ABSTRACT: The contribution of hereditary factors in basal cell carcinoma of the skin has not been well defined at the population level. We aimed to assess the hereditary component in basal cell carcinoma by comparing its occurrence in monozygotic and dizygotic twin pairs. The Finnish Twin Cohort, comprising 12,941 adult, like-sex twin pairs with established zygosity and resident in Finland in 1975, was linked with the Finnish Cancer Registry. We identified 335 twin pairs in which at least one twin had basal cell carcinoma diagnosed between 1953 and 1996. Standardized incidence ratios, concordances, tetrachoric correlations and pairwise relative risks were computed by standard methods. Components of variance in liability were estimated by structural equation modelling. There was an elevated risk of basal cell carcinoma for the co-twin of a diseased twin, but no difference in risk by zygosity. During the prospective follow-up in 1976-96, the probandwise concordance was 7.7% in monozygotic and 7.0% in dizygotic pairs. Model fitting indicated that genetic factors were not needed to account for the distribution of basal cell carcinoma in twin pairs. These results confirm the major role of environmental factors in the aetiology of basal cell carcinoma.
British Journal of Cancer 01/1999; 78(11):1516-20. · 5.04 Impact Factor
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ABSTRACT: To investigate the feasibility of topical psoralen PUVA (sensitization in photosensitizing psoralen drug + UVA radiation) treatment of oral lichenoid lesions (OLL).
A total of 16 patients with OLL were treated using a 0.01% trioxsalen ointment and UVA doses in the 0.09 to 1.80 J/cm2 range. The average number of sessions was 8.7 and a mean cumulative irradiation dose was 4.25 J/cm2.
A marked-to-complete healing occurred in 3 to 16 (19%) patients immediately after therapy, in 4 of 14 (29%) after 3 months, and in 5 of 14 (38%) after 14 months, respectively. Of the 16 subjects with OLL, five were diagnosed as oral lichen planus (OLP) and 11 were classified as oral lichenoid reaction (OLR). Post-PUVA amelioration rate in patients with genuine OLP (4 of 5, 80%) was superior to that in patients with OLR (1 of 9, 11%).
Topical trioxsalen photosensitization can be used in mouth-PUVA treatment, and lichen planus is a main indication for this therapy.
Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics 12/1997; 84(5):502-5. · 1.46 Impact Factor
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ABSTRACT: To investigate the relationship between erythemal sensitivity of the skin to UV radiation and epidermal urocanic acid (UCA) concentration, 45 healthy volunteers of anamnestic skin phototypes (ASP) 1-IV were studied. In 16 of the subjects, we analyzed UCA photoisomerization after graded UVB exposures. The median and mean total UCA concentration in unirradiated skin was 22.4 and 35.3 nmol/cm2, and no statistically significant difference in total UCA concentrations was detectable either between ASP I through II and III through IV or between the phototested skin type (PSP) groups 1 through 2 and 3 through 4. The relative amount of the cis-isomer varied between 3 and 35%, with median and mean values of 7 and 12%, respectively. No statistically significant difference in absolute or relative cis-UCA concentrations was detectable between ASP I through II and III through IV, but a significantly lower absolute (P < 0.009) and relative (P < 0.002) cis-UCA concentration in unirradiated skin was recorded in PSP groups 1 through 2, compared to types 3 through 4. In all tested subjects, an erythemally weighted dose of 1 mJ/cm2 sufficed to cause trans- to cis-UCA isomerization. When comparing photosensitive (skin phototype I) and phototolerant (phototypes III and IV) individuals, who were irradiated with a reference 5 mJ/cm2 UV dose or with fractions of 0.1-1.0 of their individual minimal erythema dose values, no skin phototype-dependent difference in ability to photoisomerize was discernible.
Photochemistry and Photobiology 05/1997; 65(5):862-5. · 2.41 Impact Factor
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ABSTRACT: Urocanic acid (UCA) is formed in the epidermis where it accumulates to be converted from trans- to cis-UCA by ultraviolet (UV) radiation. The two isomers modulate immune functions in several experimental systems. In particular, cis-UCA has been shown to induce antigen-specific immune tolerance, but the molecular mechanism of this effect is unknown. The present investigation was instituted to disclose any effect of UCA isomers on the cellular expression of the costimulatory antigens CD80 (B7/BB-1) and CD28. CD80 expression was efficiently induced in monocytic (CD14+) cells by human interferon-gamma, while CD28 levels on lymphocytes remained unchanged, as detected by flow cytometry. Neither UCA isomer showed any effect on the expression patterns of these costimulatory molecules. The results obtained suggest that the mode of action for epidermal UCA-induced tolerogenesis may not involve modulation of CD80 (B7/BB-1) or CD28 expression.
Archives for Dermatological Research 10/1996; 288(10):570-4. · 2.28 Impact Factor
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ABSTRACT: In order to investigate the mechanism of urocanic acid (UCA)-mediated immune modulation, we studied the effect of cis- and trans-UCA on interleukin-1 beta and tumour necrosis factor-alpha production by human peripheral blood monocytes, using immunospecific ELISA techniques. Trans-UCA augmented the interleukin-1 beta production and inhibited tumour necrosis factor-alpha production in a dose-dependent manner, whereas cis-UCA had no effect on the secretion of these cytokines by phorbol myristate acetate or lipopolysaccharide-stimulated monocytes. This is a novel example of trans-UCA mediating a biological effect, a finding earlier reported for cyclic adenosine monophosphate up-regulation in human fibroblasts by Palaszynski and coworkers and for human natural killer cell inhibition by ourselves. Our data suggest an important role for trans-UCA as an immunomodulator in the skin.
Acta Dermato Venereologica 08/1994; 74(4):266-8. · 3.18 Impact Factor
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ABSTRACT: To compare previously used protocols for ultraviolet (UV)-induced suppression of contact hypersensitivity in mice, and to develop an optimized protocol for C3H mice, the effect of 3 different allergens, varying allergen concentrations in the induction or challenge phase, local and distant sites of allergen application in respect to irradiation site, 2 mouse substrains and 2 different light sources was studied. A concentration of 0.5% of oxazolone (OXA) gave a slightly better contact sensitization than a 1% concentration of trinitrochlorobenzene (TNCB). Titration experiments revealed that for both OXA and TNCB, a 1% sensitization concentration was optimal, while the optimal challenge concentration was 0.5% for OXA and 1% for TNCB. The magnitude of the resulting contact sensitization was not influenced by either the mouse substrain (C3H/HeJ or C3H/HeN) or the site of allergen application (back or belly), but application of fluorescein isothiocyanate to the ears only produced weak sensitization. A standard UVB dose of 1.3 kJ/m2 suppressed TNCB contact sensitivity to a greater extent than that of OXA. A similar degree of UV-induced suppression was obtained with a given UVB dose, irrespective of a 50-fold difference in the concomitant UVA dose. Based on our results, a proper protocol of contact sensitization for UV-induced immunosuppression in C3H mice includes sensitization with 0.5% OXA on either the mouse back or belly, ear challenge with 0.5% OXA and ear swelling reading 24 h after challenge.
Photodermatology Photoimmunology and Photomedicine 07/1994; 10(3):106-10. · 1.30 Impact Factor
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ABSTRACT: UV irradiation has been reported to influence NK cell function both in vitro and in vivo. Since urocanic acid may mediate UV-induced immune modulation we tested the effect of trans- and cis-urocanic acid (UCA) on the cytotoxic activity of human peripheral blood lymphocytes against the erythroleukemic target cell line K562 in vitro. Trans-UCA was found to be a strong inhibitor of NK cell activity whereas cis-UCA had no effect. Trans-UCA also partially inhibited cytotoxic function of IL-2-activated NK cells and reduced IL-2-induced activation of NK cells. This is the first report describing trans-UCA to be active, and cis-UCA inactive, in regulating an immune function. In the skin, a decrease in epidermal trans-urocanic acid concentration by UV radiation could produce a favorable milieu for NK cell activity, and thus counteract the impairment of antigen-specific immune surveillance, induced by increased cis-urocanic acid concentrations.
Experimental Dermatology 05/1994; 3(2):61-5. · 3.54 Impact Factor
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ABSTRACT: The photoisomerization characteristics of urocanic acid (UCA) were studied by using both a narrow-band monochromator and 4 broad-band phototherapy devices. The latter included 2 ultraviolet B (UVB) irradiators with different emission spectra, a black-light UVA source and a long-range UVA emitter. The experiments were performed by irradiating trans-UCA in quartz cuvettes or in petri dishes at a pH and area concentration corresponding to human skin conditions and measuring the generated amount of cis-UCA by liquid chromatography. The exposure time for 50% trans-->cis isomerization was in the range of typical clinical in vivo exposure times for 2 UVB sources and for the black-light UVA irradiator, but for the long-wave UVA emitter the time for 50% isomerization greatly exceeded any typical in vivo exposure time. The wavelength at which maximal UCA photoisomerization took place varied from one radiation source to another, being 296 nm, 312, nm, 320 nm and 342 nm in the different cases. When an isomerization action spectrum derived from the narrow-band irradiation was integrated with the CIE standard action spectrum for human skin erythema, it was found that, in relation to erythemal effectiveness, the wavelengths between 310 and 340 nm isomerized UCA most efficiently.
Photodermatology Photoimmunology and Photomedicine 02/1994; 10(1):13-6. · 1.30 Impact Factor
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ABSTRACT: The long-term effects of psoriasis heliotherapy were studied in a randomized cross-over trial with a 2-year follow-up. We allocated 95 patients randomly to receive a 4-week heliotherapy course, either at the onset or in the middle of the follow-up period. After a highly significant immediate alleviation of psoriasis about 50% of the patients still had a reduction of psoriasis 6 months later and about 25% one year later. A favourable carry-over treatment effect was still observed during the second follow-up year. Taking advantage of the cross-over design, the effect of heliotherapy was calculated to be statistically significant during the first follow-up year, and the apparent long-term alleviation of psoriasis after the heliotherapy was reflected in a significant period effect. The alleviation of psoriasis was accompanied by a significant decrease in the use of antipsoriatic treatments.
Acta Dermato Venereologica 11/1993; 73(5):388-92. · 3.18 Impact Factor
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ABSTRACT: The xanthine/xanthine oxidase dependent chemiluminescence was enhanced both by lucigenin and linoleate to create a sensitive, specific, and rapid chemiluminescent method for superoxide dismutase (SOD) activity determination. A pH optimum at around 10.0 was found both for the chemiluminescence and its inhibition by SOD. At this pH, a linear inhibition response to concentrations from 0.01 to 100 ng/ml of bovine Cu,Zn SOD could be established, with a 50% inhibitory concentration of 0.75 ng/ml. As little as 0.17 fmol of Cu,Zn SOD per test can be detected. With a slightly lower sensitivity, the method is operative at pH 7.4, too. Both Cu,Zn SOD and Mn SOD can be assayed. The rationale of the assay is in combining a superoxide-producing enzymatic system with linoleate amplification to enhance the sensitivity of the chemiluminescence to inhibition by SOD activity. Applicability of the method to biological samples was tested with a standard addition experiment.
Free Radical Biology and Medicine 06/1993; 14(5):457-61. · 5.42 Impact Factor
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ABSTRACT: The role of cytokines and arachidonic acid metabolites in the regulation of IgE production in healthy persons and in atopic dermatitis patients with elevated IgE levels was studied. Interleukin-4 (IL-4) induced IgE production in peripheral blood mononuclear cells (PBMCs) of all donors, and no significant difference was found between the amounts of IgE produced by healthy persons and atopic dermatitis patients. Similarly, recombinant interferon (IFN)-alpha and IFN-gamma, as well as IL-2, inhibited IL-4-induced IgE production to a similar extent in both study groups. To evaluate the role of arachidonic acid (AA) metabolites in the regulation of IgE production, we added indomethacin, an inhibitor of the cyclooxygenase pathway, or nordihydroguaiaretic acid (NDGA), an inhibitor of the lipoxygenase pathway, to IL-4-treated cultures. Both indomethacin and NDGA strongly inhibited IL-4-induced IgE production. They also inhibited IL-4-induced IgG4 synthesis. No significant difference in the amount of inhibition was found between the two study groups. We were unable to restore the NDGA-induced inhibition of IgE-production by adding leukotrienes B4, C4, D4, or 5-HETE to the NDGA-treated cultures. PGE2 also failed to restore the indomethacin-mediated inhibitory effect. Consequently, NDGA- and indomethacin-mediated inhibitory effects do not appear to be mediated by any single factor studied. Collectively, our results show IFNs and IL-2 to be similar in effect in the modulation of IL-4-induced IgE synthesis in healthy and atopic persons.(ABSTRACT TRUNCATED AT 250 WORDS)
Allergy 05/1993; 48(3):189-95. · 6.27 Impact Factor
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ABSTRACT: The effect of heliotherapy on psoriasis skin lesions and arthritis was studied in a trial comprising 4 weeks of therapy in the Canary Islands and a 6-month follow-up period. A total of 373 patients participated in the heliotherapy and 361 patients completed the follow-up period. The severity of skin lesions was evaluated using a psoriasis severity index (PSI), and that of the arthropathy by using an arthritis index (AI). During heliotherapy, the PSI decreased significantly from the initial median value of 4.5 to the final value of 0.2. A reduction in the PSI of at least 75% was achieved in 84% of the patients. Guttate psoriasis improved significantly better than plaque-type or erythrodermic psoriasis. There was no correlation between skin type and improvement. Initially, 129 patients had symptoms of arthritis. During heliotherapy, the AI decreased significantly from the initial median value of 6 to the final value of 2. The median time until starting another treatment after heliotherapy was 80 days, and the PSI had returned to its original value in 49% of the patients in 6 months. In patients with joint symptoms the AI returned to the pretreatment level within 6 months. A 4-week heliotherapy period effectively cleared psoriasis, alleviated joint symptoms, and reduced both morbidity and treatment requirement to a considerable extent in the ensuing 6-month period.
British Journal of Dermatology 03/1993; 128(2):172-7. · 3.67 Impact Factor
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ABSTRACT: The ultraviolet (UV) radiation doses received by 270 psoriasis patients were studied during 4-week climate therapy periods in November, March or April in the Canary Islands. The daily total solar UV radiation (ambient radiation load, ARL) was measured using frequent readings with a Robertson-Berger sunburning ultraviolet (SUV) meter. A daily personal radiation load (PRL) was calculated for each patient, using sun exposure diary data. To measure the cumulative UV exposure of particular skin sites (skin site dose, SSD), 10 patients wore polysulphone UV dosimeters. The daily ambient radiation load (ARL) ranged from 2.9 to 8.9 erythemal units (EU); the cumulative ARL for a 4-week treatment period was 182.6 EU. The mean daily personal radiation load (PRL), calculated separately for each week of the treatment period, was from 2.5 to 5.6 EU; the mean total 4-week PRL was 118.0 EU, being about 65% of the ARL. The 4-week cumulative skin site dose (SSD) varied between 22.2 and 63.3% (mean 41.2%) of the corresponding personal radiation load (PRL).
Photodermatology Photoimmunology and Photomedicine 03/1992; 9(1):40-3. · 1.30 Impact Factor
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ABSTRACT: A noninvasive Finn Chamber sampling method and HPLC analysis were used to determine epidermal urocanic acid (UCA) concentrations of psoriasis patients during 4 weeks of heliotherapy on the Spanish Canary Islands and a follow-up period of 8 weeks. During heliotherapy the epidermal cis-UCA concentration increased from a mean initial value of 0.2 nmol/cm2 to a mean final value of 2.9 nmol/cm2. The total UCA concentration decreased during the first week of heliotherapy from an initial value of 5.5 nmol/cm2 to a nadir of 2.0 nmol/cm2. Thereafter, a steady increase was recorded in the total UCA level, with a maximum of 10.2 nmol/cm2 in week 2 of the post-treatment follow-up period. Suberythemal sun exposures caused near-maximal UCA isomerization, and during heliotherapy the cis isomer constituted 63.7-74.3% of the total UCA concentration. Clinical response of psoriasis to heliotherapy, however, seemed to be independent of UCA isomer levels.
Acta Dermato Venereologica 02/1992; 72(3):231-3. · 3.18 Impact Factor
