Exopolysaccharides Isolated from Milk Fermented with Lactic Acid Bacteria Prevent Ultraviolet-Induced Skin Damage in Hairless Mice.

BACKGROUND: We studied the mechanism by which fermented milk ameliorates UV-B-induced skin damage and determined the active components in milk fermented with lactic acid bacteria by evaluating erythema formation, dryness, epidermal proliferation, DNA damage and cytokine mRNA levels in hairless mice exposed to acute UV-B irradiation. METHODS: Nine week-old hairless mice were given fermented milk (1.3 g/kg BW/day) or exopolysaccharide (EPS) concentrate (70 mg/kg BW/day) orally for ten days. Seven days after fermented milk or EPS administration began, the dorsal skin of the mice was exposed to a single dose of UV-B (20 mJ/cm²). RESULTS: Ingestion of either fermented milk or EPS significantly attenuated UV-B-induced erythema formation, dryness and epidermal proliferation in mouse skin. Both fermented milk and EPS were associated with a significant decrease in cyclobutane pyrimidine dimers and upregulated mRNA levels of xeroderma pigmentosum complementation group A (XPA), which is involved in DNA repair. Furthermore, administration of either fermented milk or EPS significantly suppressed increases in the ratio of interleukin (IL)-10/IL-12a and IL-10/interferon-gamma mRNA levels. CONCLUSION: Together, these results indicate that EPS isolated from milk fermented with lactic acid bacteria enhanced DNA repair mechanisms and modulated skin immunity to protect skin against UV damage.

Radioprotective Effects of Heat-Killed Mycobacterium Tuberculosis in Cultured Cells and Radiosensitive Tissues.

BACKGROUND: Exposure to ionizing radiation (IR) often causes severe damage to radiosensitive tissues, which limits the use of radiotherapy in cancer patients. Novel safe and effective radioprotectant is urgently required. It has been reported toll like receptor 2 (TLR2) plays a critical role in radioresistance. In this study, we demonstrated the protective effects of Heat-Killed Mycobacterium tuberculosis (HKMT), a potent TLR2 agonist, against IR. METHODS: Cell survival and apoptosis were determined by CCK-8 assay and Annexin V assay, respectively. An immunofluorescence staining assay was used to detect the translocation of nuclear faktor-kappa beta (NF-kB) p65. Tissue damage was evaluated by Haematoxilin-Eosin (HE) staining assay. We also used a flow cytometry assay to measure the number of nucleated cells and CD34+ hemopoietic stem cells in bone marrow. A western blot assay was used to detect the changes of proteins involving TLR signaling pathway. RESULTS: We found that HKMT increased cell viability and inhibited cell apoptosis after irradiation. HKMT induced NF-kB translocation and activated Erk1/2, p38 signaling pathway. HKMT also protected bone marrow and testis from destruction. Radiation-induced decreases of nucleated cells and CD34+ hemopoietic stem cells in bone marrow were also inhibited by HKMT treatment. We found that radiation caused increase of inflammatory cytokines was also suppressed by HKMT. CONCLUSION: Our data showed that HKMT exhibited radioprotective effects in vivo and in vitro through activating NF-kB and MAPK signaling pathway, suggesting a potential of HKMT as novel radioprotector.

Relationship between UV-irradiated HaCaT cell cytokines and Th1/Th2 imbalance.

We have previously found that an imbalance of Tc1/Tc2 T cell subtypes in vivo impacts the development of photodermatitis. The aim of this study was to investigate the relationship between cytokines derived from keratinocytes exposure to UV and the imbalance of Th subgroups. We used different doses of UVA and UVB to irradiate HaCaT cells. Twelve hours after irradiation, the expression of IL-10R, IL-4R, IL-12R, and IFN-γR proteins was observed using the S-P method, and the percentage of positive cells calculated. Protein levels of the respective ligands in the supernatant was measured by ELISA. Our results showed low levels of expression of the interrogated proteins in unirradiated HaCaT cells, and little or no expression could be detected in the supernatant. Little or no expression was also observed for IL-12R and IFN-γR 12 h after UVA or UVB irradiation. However, the expression of IL-10R and IL-10 was upregulated 12 h following UVB irradiation, as well as following lower dose UVA irradiation. In contrast, higher dose UVA decreased the expression of IL-10R and IL-10. The expression of IL-4R was increased following high doses of UVA and UVB irradiation, whereas no expression was observed after lower dose UV exposure. There was no change in IL-4 secretion into the supernatant. Our results demonstrate that the effects of UV exposure on keratinocyte-derived cytokines are different according to the doses of irradiation and the types of cytokines, and suggest that keratinocyte-derived cytokines after UV exposure might cause an imbalance of Th1/Th2.

Systemically elevated Th1-, Th2- and Th17-associated chemokines in psoriasis vulgaris before and after ultraviolet B treatment.

Chemokines may contribute to the systemic inflammation that is linked to the increased risk of co-morbidities in patients with psoriasis. The aim of this study was to investigate circulating chemokines in patients with psoriasis and their relationship to disease severity. Analysis of plasma levels of chemokines in patients with psoriasis before narrowband ultraviolet B (UVB) therapy revealed increased expression of Th1-associated CXCL9 and -10, Th2-associated CCL17 and CCL22, and Th17-associated CCL20. CCL20 correlated with disease severity. UVB therapy reduced skin symptoms, but did not affect the chemokine levels in plasma. Anti-CD3 and anti-CD28-mediated activation of peripheral blood mononuclear cells (PBMCs) caused a higher secretion of Th2 cytokine interleukin (IL)-13 by PBMCs from patients with psoriasis than from healthy controls. The sustained high expression of inflammatory chemokines is a potential link to systemic inflammation in psoriasis. UVB therapy may be a more effective treatment of local rather than systemic inflammation.

UV irradiation of immunized mice induces type 1 regulatory T cells that suppress tumor antigen specific cytotoxic T lymphocyte responses.

We previously showed that exposure to UV radiation after immunization suppresses Th1 and Th2 immune responses, leading to impaired Ab and allo-immune responses, but the impact of UV radiation after immunization on anti-tumor immune responses mediated by tumor-specific CD8(+) T cell responses remains less clear. Furthermore, the exact phenotypic and functional characteristics of regulatory T cell population responsible for the UV-induced immunosuppression still remain elusive. Using the MBL-2 lymphoma cell line engineered to express OVA as a surrogate tumor Ag, here we demonstrate that UV irradiation after tumor Ag-immunization suppresses the anti-tumor immune response in a manner dependent on the immunizing Ag. This suppression was mediated by interleukin (IL)-10 released from CD4(+) CD25(+) T cells, by which impaired the induction of cytotoxic T lymphocytes (CTL) able to kill Ag-expressing tumor cells. In addition, we generated a panel of T cell clones from UV-irradiated and non-irradiated mice, and all of the clones derived from UV-irradiated mice had a Tr1-type regulatory T cell phenotype with expression of IL-10 and c-Maf, but not Foxp3. These Tr1-type regulatory T cell clones suppressed tumor rejection in vivo as well as Th cell activation in vitro in an IL-10 dependent manner. Given that suppression of Ag-specific CTL responses can be induced in Ag-sensitized mice by UV irradiation, our results may imply that exposure to UV radiation during premalignant stage induces tumor-Ag specific Tr1 cells that mediate tumor-Ag specific immune suppression resulting in the promotion of tumor progression.

Immunological modulation of the Th1/Th2 shift by ionizing radiation in tumors (Review).

Extensive evidence has documented that the balance between cytokines from T helper type 1 (Th1) and type 2 (Th2) cells is disrupted in the tumorigenic microenvironment compared with immunocompetent individuals. Ionizing radiation (IR) has been reported to markedly modulate the Th1/Th2 polarization in a concentration­dependent manner. In the present review article, the immune modulation of Th1/Th2 and the IR­induced crosstalk of the Th1/Th2 shift with immunocytes and tumor cells are summarized. The involvement of the Th1/Th2 shift in post­radiotherapy complications is highlighted. Specifically, high­dose IR has been shown to promote the Th2 shift, leading to an immunosuppressive cytokine network, while the impact of low­dose IR remains controversial. The IR­induced modulation of the Th1/Th2 shift is mediated by tumor cells and multiple immunocytes, including dendritic cells, tumor­associated macrophages, cytotoxic T lymphocytes and natural killer cells. However, the excessive production of pro­inflammatory factors, such as IFN­Î³ and IL­2, by Th1 cells, aggravates the clinical side­effects of radiotherapy, including radiation­induced lung and intestinal injury, radiation encephalopathy, as well as other complications. Therefore, further research into the underlying mechanism is required to confirm the potential applicability of the Th1/Th2 shift combined with IR in the treatment of malignant tumors.

Alterations of serum Th1 and Th2 chemokines by combination therapy of interferon-gamma and narrowband UVB in patients with mycosis fungoides.

BACKGROUND: Mycosis fungoides (MF) is a T cell neoplasm with elevation of serum Th2 chemokines. Although interferon-gamma (IFN-gamma) administration and narrowband-UVB (NB-UVB) phototherapy are used for the treatment of MF, a combination therapy of these two modalities is not fully established. OBJECTIVES: To define whether the combination of IFN-gamma and NB-UVB affects the balance of serum levels of Th1 and Th2 chemokines in patients with MF. METHODS: Twelve patients with MF received intravenous or intramuscular injections of recombinant IFN-gamma (rIFN-gamma) or natural IFN-gamma (nIFN-gamma) in combination with NB-UVB phototherapy. As control, three MF patients were treated with NB-UVB monotherapy. At the beginning and cessation of therapy, the concentrations of serum Th2 chemokines, TARC/CCL17 and MDC/CCL22, and Th1 chemokines, IP-10/CXCL10 and MIG/CXCL9 were measured by ELISA. RESULTS: Before treatment, not only Th2 chemokines but also Th1 chemokines were elevated in the patients. Whereas no significant changes were observed in the levels of TARC and MDC, IP-10 and MIG were further elevated by the combination of IFN-gamma and NB-UVB. On the other hand, NB-UVB monotherapy did not change the level of either Th1 or Th2 chemokine. CONCLUSIONS: The combination of IFN-gamma and NB-UVB elevated serum Th1 chemokines but unaffected Th2 chemokines. Since NB-UVB monotherapy could not affect the chemokine levels, the effect of the combination therapy is attributable to IFN-gamma. Given the role of Th1 chemokines for tumor-attacking T cell recruitment at the early stage of MF, the therapy may exert a beneficial effect for early MF.

Acute and persisting Th2-like immune response after fractionated colorectal gamma-irradiation.

AIM: To investigate if an immune imbalance may account for the development and progression of chronic radiation enteritis. We analyzed the Th1/Th2 immune response profile early and 6 mo after fractionated colorectal irradiation. METHODS: A rat model of fractionated colorectal gamma-irradiation (4-Gy fractions, 3 fractions per week) was designed to investigate the effects of cumulative dose on inflammatory mediators (cytokines and chemokines) and immune response (Th1/Th2 profile and immunosuppressive mediator IL-10) during acute (early) response and 6 mo after the end of fractionated irradiation (chronic response). Analyses were performed 1 d after the cumulative doses of 16 Gy and 36 Gy and 1 d, 3 d, and 26 wk after the cumulative dose of 52 Gy. RESULTS: Without causing histological damage, fractionated radiation induced elevated expression of IL-1beta, TNFalpha, MCP-1, and iNOS in distal colonic mucosa during the early post-irradiation phase. At that time, a Th2 profile was confirmed by expression of both the Th2-specific transcription factor GATA-3 and the chemokine receptor CCR4 and by suppression of the Th1 cytokine IFNgamma/IP-10 throughout the irradiation protocol. After 6 mo, despite the 2-fold reduction of iNOS and MCP-1 levels, the Th2 profile persisted, as shown by a 50% reduction in the expression of the Th1 transcription factor T-bet, the chemokine receptor CCXCR3, and the IFNgamma/STAT1 pathway. At the same time-point, the immunosuppressive IL-10/STAT3 pathway, known to regulate the Th1/Th2 balance, was expressed, in irradiated rats, at approximately half its level as compared to controls. This suppression was associated with an overexpression of SOCS3, which inhibits the feedback of the Th1 polarization and regulates IL-10 production. CONCLUSION: Colorectal irradiation induces Th2 polarization, defective IL-10/STAT3 pathway activation and SOCS3 overexpression. These changes, in turn, maintain a immunological imbalance that persists in the long term.

Impairment of natural killer (NK) cells is an important factor in a weak Th1-like response in irradiated mice.

In whole-body-irradiated (WBI) mice, levels of the canonical Th1 cytokine IFN-gamma (IFNG) have been shown to be markedly reduced, resulting in a Th1/Th2 imbalance. In this study, the influence of natural killer (NK) cells on the balance of this Th1/Th2 immune response was evaluated in WBI mice. Although NK cells are one of the types of cells that secreteIFN-gamma, NK cell activity tends to be minimal, even at 7 weeks after irradiation. In NK cell-depleted mice, the levels of Th1-related cytokines were lower than those of the control mice and were correlated with lower IgG2a production and elevated IgE and IgG1 production. These results indicated that NK cells have a crucial role in the final differentiation of Th cells into Th1 cells. The impairment of NK cells in the WBI mice was confirmed by the observation that NK cells from the WBI mice induced a decrease in the generation of IFN-gamma by the NK cell-depleted spleen lymphocytes from normal mice. Also, the WBI mice that received NK cells obtained from the normal mice generated more IgG2a, IL12 and IFN-gamma. Our results indicate that the impairment of NK cells is an important factor in the reduced Th1-like response in irradiated mice.

Radiation-induced decrease of CD8+ dendritic cells contributes to Th1/Th2 shift.

Exposure to ionizing radiation (IR) often reduce the helper T (Th) 1 like function, resulting in a Th1/Th2 imbalance, which could affect the efficacy of cancer radiotherapy. As the most potent antigen presenting cells, dendritic cells (DC) can be divided into several subsets with specialized function. However, there is no literature covering the changes of DC subsets and their roles in immune regulation in response to IR. In the present study, we were aimed to investigate the changes of DC subsets after IR and its relationship with Th1/Th2 immunity. We found a significant decrease of BDCA3+DC in the blood of patients treated with radiotherapy. CD8+DC, a mouse equivalent of human BDCA3+DC, was also found decreased in mice spleen, peripheral blood and lymph node tissues after irradiation. As CD8+DC mainly induce Th1 immunity, we tested the changes of Th1/Th2 response and found that IR caused a repression of Th1 immunity, indicating a possible role of CD8+DC in radiation-induced Th1/Th2 imbalance. We also found that a CD8+DC-inducing cytokine, Fms-like tyrosine kinase 3 ligand (FLT3 ligand), restored CD8+DC and reversed Th1/Th2 shift. And then we found that bone marrow cells from irradiated mice differentiated into less CD8+DC, which was also protected by FLT3 ligand. In conclusion, our data showed that IR induced a decrease of CD8+DC and Th1/Th2 shift, which was reversed by Flt3 ligand treatment, suggesting a novel mechanism for radiation-induced immunosuppression.

Eosinophil Cationic Protein in Patients with Differentiated Thyroid Cancer Treated with Radioactive Iodine 131.

Published data indicate the involvement of eosinophil granulocytes and eosinophil cationic protein (ECP) in tumor defense. The aim of this study was to analyze serum ECP concentrations in patients with differentiated thyroid cancer (DTC) before, 3 days and 7 days after radioactive iodine (131-I) therapy. Association of ECP concentrations with histological type of tumor, stage of disease and/or levels of selected T-helper 2 (Th2) cytokines was examined. The study population included 17 DTC patients and 10 control subjects. ECP was measured by fluoroimmunoassay (FIA). Th2 (cytokines interleukin 4 (IL-4), interleukin 5 (IL-5), and interleukin 13 (IL-13)) were determined by enzyme-linked immunosorbent assays (ELISA). We found that ECP values in DTC patients before radioactive iodine therapy were approximately two-fold higher than in the controls, but the difference was statistically significant only if the patients with DTC and associated Hashimoto thyroiditis (HT) were included. There was no correlation between the serum concentrations of IL-5 and ECP. Radioactive iodine therapy led to a decrease in serum ECP level which did not follow the decline in serum protein levels. Additional studies are needed to determine the significance of these findings.

Establishment of murine model of allergic photocontact dermatitis to ketoprofen and characterization of pathogenic T cells.

BACKGROUND: Ketoprofen is well known to evoke the allergic type of photocontact dermatitis when it is applied to the skin and irradiated with ultraviolet A (UVA) light. OBJECTIVE: We aimed to establish a murine model of this photosensitivity and to characterize pathogenic T cells concerned with the sensitivity. METHODS: Various strains of mice were sensitized on two consecutive days by application of ketoprofen to the shaved abdomen and irradiation of the skin with UVA. Five days later, they were elicited with ketoprofen plus UVA on the earlobes. Immune lymph node cells and epidermal cells from the challenged sites were analyzed by RT-PCR. RESULTS: Mice were successfully sensitized and challenged with 4% and 2% ketoprofen, respective, plus UVA at 20J/cm2. The responses in H-2k mice were higher than those in the other strains examined. Immune lymph node CD4+ or CD8+ cells from ketoprofen-photosensitized H-2k mice were transferred i.v. to naïve syngeneic recipients. Mice receiving CD4+ but not CD8+ cells exhibited ketoprofen photosensitivity, but transference of both CD4+ and CD8+ cell populations was more effective. Lymph node cells from photosensitized mice expressed high levels of mRNA for Th2 cytokine (IL-4) and Th2 chemokine receptor (CCR4) as well as Th1 cytokine (IFN-gamma) and Th1 chemokine receptor (CXCR3), as assessed by RT-PCR. In addition, epidermal cells from challenged earlobes expressed increased levels of both Th1 (TARC) and Th2 (Mig) chemokines. CONCLUSION: It is considered that not only Th1 but also Th2 cells participate in the pathogenesis of murine photocontact dermatitis to ketoprofen.

Caffeic acid phenethyl ester modifies the Th1/Th2 balance in ileal mucosa after gamma-irradiation in the rat by modulating the cytokine pattern.

AIM: To pharmacologically modulate Th polarization in the ileum exposed to ionizing radiation by using the immuno-modulatory/apoptotic properties of Caffeic Acid Phenethyl Ester (CAPE). METHODS: Rats received CAPE (30 mg/kg) treatment ip 15 min prior to intestinal 10 Gy gamma-irradiation and once a day for a 6 d period after irradiation. Expression of genes implicated in Th differentiation in ileal mucosa (IL-23/IL-12Rbeta2), Th cytokine responses (IFN-gamma, IL-2, IL-4, IL-13), Th migratory behaviour (CXCR3, CCR5, CCR4), Th signalling suppressors (SOCS1, SOCS3), transcription factor (T-Bet, GATA-3) and apoptosis (FasL/Fas, TNF/TNFR, XIAP, Bax, caspase-3) was analyzed by RT-PCR 6 h and 7 d post-irradiation. CD4(+) and TUNEL positive cells were visualized by immunostaining. RESULTS: The expression of Th1-related cytokine/chemokine receptors (IFN-gamma, IL-2, CXCR3, CCR5) was repressed at 7 d post-irradiation while Th2 cell cytokine/chemokines (IL-4, IL-13, CCR4) were not repressed or even upregulated. The irradiation-induced Th2 profile was confirmed by the upregulation of both Th2-specific transcription factor GATA-3 and SOCS3. Although an apoptosis event occurred 6 h after 10 Gy of intestinal gamma-irradiation, apoptotic mediator analysis showed a tendency to apoptotic resistance 7 d post-irradiation. CAPE amplified apoptotic events at 6 h and normalized Bax/FasL expressions at 7 d. CONCLUSION: CAPE prevented the ileal Th2 immune response by modulating the irradiation-influenced cytokine environment and apoptosis.

[Induction of glutathione and activation of immune functions by low-dose, whole-body irradiation with gamma-rays].

We first examined the relation between the induction of glutathione and immune functions in mice after low-dose gamma-ray irradiation. Thereafter, inhibition of tumor growth by radiation was confirmed in Ehrlich solid tumor (EST)-bearing mice. The total glutathione level of the splenocytes transiently increased soon after irradiation and reached a maximum at around 4 h postirradiation. Thereafter, the level reverted to the 0 h value by 24 h postirradiation. A significantly high splenocyte proliferative response was also recognized 4 h postirradiation. Natural killer (NK) activity was also increased significantly in a similar manner. The time at which the response reached the maximum coincided well with that of maximum total glutathione levels of the splenocytes in the gamma-ray-irradiated mice. Reduced glutathione exogenously added to splenocytes obtained from normal mice enhanced the proliferative response and NK activity in a dose-dependent manner. The inhibitory effects of radiation on tumor growth was then examined in EST-bearing mice. Repeated low-dose irradiation (0.5 Gy, four times, before and within an early time after inoculation) significantly delayed the tumor growth. Finally, the effect of single low-dose (0.5 Gy), whole-body gamma-ray irradiation on immune balance was examined to elucidate the mechanism underlying the antitumor immunity. The percentage of B cells in blood lymphocytes was selectively decreased after radiation, concomitant with an increase in that of the helper T cell population. The IFN-gamma level in splenocyte culture prepared from EST-bearing mice was significantly increased 48 h after radiation, although the level of IL-4 was unchanged. IL-12 secretion from macrophages was also enhanced by radiation. These results suggest that low-dose gamma-rays induce Th1 polarization and enhance the activities of tumoricidal effector cells, leading to an inhibition of tumor growth.

Impairment of the Intrinsic Capability of Th1 Polarization in Irradiated Mice: A Close Look at the Imbalanced Th1/Th2 Response after Irradiation.

Two major CD4+ T-helper (Th) lineages are Th1 and Th2, and well balanced Th1/Th2 responses are essential for immune function. In previously published studies, it was reported that radiation induces a Th1/Th2 immune imbalance toward a Th2-dominant direction, and this imbalance may contribute to postirradiation immune dysfunction. The polarization of Th cells is driven by the cytokine milieu and controlled by intracellular regulatory pathways that respond to cytokine signaling. It is widely accepted that radiation induces cytokine aberration, however, the precise alterations of cytokines in various tissue environments have been difficult to evaluate. In addition, the effects of radiation on the intrinsic functions of Th cells remain uncharacterized. Therefore, how radiation affects Th1/Th2 balance remains somewhat unclear. To address this, we investigated the changes in the polarization capability of Th cells by isolating them from mice previously exposed to radiation and assessing the cells in an established in vitro Th polarization system. Our novel results demonstrate that prior exposure to radiation led to the persistent aberration of the inherent capability of Th cells to differentiate into Th1 and Th2 lineages. The parallel changes in expression of Th1-specific master transcription factors and the key genes in metabolic reprograming indicated that radiation affects the core components in Th1 polarization. While Th1 differentiation was impaired after irradiation, little adverse effect was observed in Th2 differentiation; both of these findings contribute to the known phenotypes of Th1/Th2 imbalance caused by radiation.

Factors effecting the Th2-like immune response after gamma-irradiation: low production of IL-12 heterodimer in antigen-presenting cells and small expression of the IL-12 receptor in T cells.

Ionizing radiation is known to reduce the helper T (Th) 1-like function, but not the Th2-like function, resulting in a Th1/Th2 imbalance. While this has been known for some time, the mechanism behind the preferential suppression of the Th1 cell activation has not yet been explained. The aim is to elucidate the mechanism in the Th cell imbalance after ionizing irradiation. C57BL/6 mice, 7 weeks old, received whole-body gamma-irradiation (WBI) of 5 Gy. In all instances, the spleen and peritoneal cells were obtained from mice 7 weeks after irradiation. To distinguish Th1 and Th2 cell function, interferon (IFN)-gamma and interleukin (IL)-4 produced by these cells were analysed by an enzyme-linked immunosorbent assay (ELISA). To isolate the primary T cells, the anti-CD90.2 microbead-conjugated antibody was used and the labelled cells were separated by magnetic cell sorting (MACS). To investigate the influence of the IL-12p70 secreted by the antigen-presenting cells, ovalbumin (OVA)-primed peritoneal adherent cells (PAC) were fixed by 1% paraformaldehyde and co-cultured with OVA-specific Th cells in the presence of supernatant of PAC culture with OVA for 16 h. IL-12 receptor, signal transducers and activators of transcription 4 (STAT4) and IFN-gamma expression in the T cells of the WBI mice were detected by reverse transcriptase-polymerase chain reaction (RT-PCR). The spleen lymphocytes of WBI mice showed a depression of IFN-gamma production against OVA, although the total IL-12 was highly secreted. However, the heterodimer IL-12, biologically active protein, was induced less in WBI mice. Although the OVA-specific Th cells were co-cultured with fixed OVA-primed PAC obtained from normal mice, the OVA-specific Th cells showed a decreased IFN-gamma secretion in the presence of the culture supernatant of the activated PAC from the WBI mice. In addition, recombinant IL-12p70 restored the cytokine balance of the OVA-specific Th cells. However the cytokine balance of primary T cells from WBI mice was not completely restored by the normal antigen-presenting cells that abundantly secrete IL-12p70. It was assumed that after WBI, the regenerated T cells also have some problems. It was then observed that the IL-12 receptor expression and intracellular levels of the STAT4 were much lower in the T cells of the WBI mice. The results suggest that the shifted response of the helper T cells after WBI exposure is due not only due to a significant suppression of the secretion of the IL-12p70 in the antigen-presenting cells, but also to the lower expression of the IL-12 receptor on T cells.

Proinflammatory and Th1 cytokine alterations following ultraviolet radiation enhancement of disease due to influenza infection in mice.

Exposure of rodents to immunosuppressive agents such as ozone, dioxin, or ultraviolet radiation (UVR) leads to increased morbidity and mortality following influenza virus infection. However, these adverse effects are not related to the suppression of virus-specific immune responses. Our laboratory showed that UVR increased the morbidity, mortality, and pathogenesis of influenza virus without affecting protective immunity to the virus, as measured by resistance to reinfection, suggesting that UVR and other immunosuppressive pollutants such as dioxin and ozone may exacerbate early responses that contribute to the pathogenesis of a primary viral infection. In the present study, we examined the mechanism of UVR-enhanced mortality in the absence of effects on virus-specific immunity and tested the hypothesis that modulation of cytokine levels was associated with increased deaths and body weight loss. BALB/c mice were exposed to 8.2 kJ/m(2) UVR and were infected 3 days later with a sublethal influenza virus infection (LD(40) of mouse-adapted Hong Kong influenza A/68, H(3)N(2)). Influx of inflammatory cells, proinflammatory cytokines, and cytokines produced by T-helper lymphocytes (Th1 and Th2) were measured in lung homogenates (LH) as well as in bronchoalveolar lavage fluid (BAL). UVR preexposure decreased the influenza-induced lymphocytic influx 5 days after infection, but did not alter macrophage and neutrophil influx into the lung, or increase virus titers significantly. Although interferon (IFN)-gamma, total interleukin (IL)-12, IL-6, and TNF-alpha were altered in mice that received UVR exposure prior to infection, no clear association was made that correlated with the UVR-induced increase in body weight loss and mortality due to influenza infection.

UV exposure alters respiratory allergic responses in mice.

We have tested the hypothesis that exposure to ultraviolet light would inhibit T helper-1 (Th1) responses and stimulate T helper-2 (Th2) responses, and that thus in a mouse model of allergic (i.e. extrinsic) asthma (using ovalbumin [OVA] as the allergen) increased symptoms would be observed, while in a model of Th1-dependent occupational asthma (in which picryl chloride is the allergen) decreased symptoms would be observed. Whereas reduced interferon (IFN)-gamma production, decreased inflammatory responses in the airways, and reduced airway reactivity to nonspecific stimuli were observed in UV-preexposed picryl chloride sensitized and challenged mice, the results in the OVA model were less clear. Increased interleukin (IL)-10 production as a result of UV exposure was observed, together with unchanged IL-4 and IFN-gamma. In addition, decreased OVA-specific immunoglobin, IgG1 and IgE, titers were noted, as well as decreased nonspecific airway hyperreactivity. Eosinophilic inflammatory responses were not influenced. The results indicate that UV exposure can have systemic effects that influence ongoing immune responses in the respiratory tract. The effects are not only restricted to immune responses that are predominantly Th1 dependent (i.e. pulmonary delayed-type hypersensitivity and IFN-gamma production in response to picryl chloride) but also to immune response that are predominantly Th2 dependent, i.e. decreased specific IgE titers.

Does exposure to UV radiation induce a shift to a Th-2-like immune reaction?

In addition to being the primary cause of skin cancer, UV radiation is immune suppressive and there appears to be a link between the ability of UV to suppress the immune response and induce skin cancer. Cytokines made by UV-irradiated keratinocytes play an essential role in activating immune suppression. In particular, we have found that keratinocyte-derived interleukin (IL)-10 is responsible for the systemic impairment of antigen-presenting cell function and the UV-induced suppression of delayed-type hypersensitivity (DTH). Antigen presentation by splenic adherent cells isolated from UV-irradiated mice to T helper-1 type T (Th1) cells is suppressed, whereas antigen presentation to T helper-2 type T (Th2) cells is enhanced. The enhanced antigen presentation to Th2 cells and the impaired presentation to Th1 cells can be reversed in vivo by injecting the UV-irradiated mice with monoclonal anti-IL-10 antibody. Furthermore, immune suppression can be transferred from UV-irradiated mice to normal recipients by adoptive transfer of T cells. Injecting the recipient mice with anti-IL-4 or anti-IL-10 prevents the transfer of immune suppression, suggesting the suppressor cells are Th2 cells. In addition, injecting UV-irradiated mice with IL-12, a cytokine that has been shown to be the primary inducer of Th1 cells, and one that prevents the differentiation of Th2 cells in vivo, reverses UV-induced immune suppression. These findings support the hypothesis that UV exposure activates IL-10 secretion, which depresses the function of Th1 cells, while enhancing the activity of Th2 cells.