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1.
Cancer Res ; 73(16): 5169-82, 2013 Aug 15.
Article in English | MEDLINE | ID: mdl-23946473

ABSTRACT

The actin cytoskeleton is a potentially vulnerable property of cancer cells, yet chemotherapeutic targeting attempts have been hampered by unacceptable toxicity. In this study, we have shown that it is possible to disrupt specific actin filament populations by targeting isoforms of tropomyosin, a core component of actin filaments, that are selectively upregulated in cancers. A novel class of anti-tropomyosin compounds has been developed that preferentially disrupts the actin cytoskeleton of tumor cells, impairing both tumor cell motility and viability. Our lead compound, TR100, is effective in vitro and in vivo in reducing tumor cell growth in neuroblastoma and melanoma models. Importantly, TR100 shows no adverse impact on cardiac structure and function, which is the major side effect of current anti-actin drugs. This proof-of-principle study shows that it is possible to target specific actin filament populations fundamental to tumor cell viability based on their tropomyosin isoform composition. This improvement in specificity provides a pathway to the development of a novel class of anti-actin compounds for the potential treatment of a wide variety of cancers.


Subject(s)
Actin Cytoskeleton/metabolism , Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Neoplasms/metabolism , Animals , Apoptosis/drug effects , Cell Differentiation/drug effects , Cell Line , Cell Line, Tumor , Cell Movement/drug effects , Cell Survival/drug effects , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Melanoma/drug therapy , Mice , NIH 3T3 Cells , Neoplasms/pathology , Neuroblastoma/drug therapy , Tropomyosin/antagonists & inhibitors , Tropomyosin/metabolism , Up-Regulation/drug effects
2.
Photochem Photobiol Sci ; 11(1): 173-9, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21968628

ABSTRACT

Immunosuppression attributed mainly to the UVB (290-320 nm) waveband is a prerequisite for skin cancer development in mice and humans. The contribution of UVA (320-400 nm) is controversial, but in mice UVA irradiation has been found to antagonise immunosuppression by UVB. In other studies of photoimmune regulation, protection mediated via oestrogen receptor-ß signalling was identified as a normal endogenous defence in mice, and was shown to depend on UVA irradiation. A gender bias in photoimmune responsiveness was thus suggested, and is tested in this study by comparing the UV-induced inflammatory and immune responses in male and female hairless mice. We report that male mice, which show greater skin thickness than females, developed a less intense but slower resolving sunburn inflammatory oedema, correlated with reduced epidermal expression of pro-inflammatory IL-6 than females following solar simulated UV (SSUV, 290-400 nm) exposure. On the other hand, the contact hypersensitivity reaction (CHS) was more severely suppressed by SSUV in males, correlated with increased epidermal expression of immunosuppressive IL-10. Exposure to the UVB waveband alone, or to cis-urocanic acid, suppressed CHS equally in males and females. However, whereas UVA irradiation induced immunoprotection against either UVB or cis-urocanic acid in females, this protection was significantly reduced or abrogated in males. The results indicate that males are compromised by a relative unresponsiveness to the photoimmune protective effects of UVA, alone or as a component of SSUV. This could explain the known gender bias in skin cancer development in both mice and humans.


Subject(s)
Immunosuppression Therapy , Inflammation/etiology , Sex Factors , Ultraviolet Rays , Animals , Female , Male , Mice
3.
Photochem Photobiol Sci ; 11(2): 309-17, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22048469

ABSTRACT

Hypoxia inducible factor-1α (HIF-1α), a ubiquitous inducible oxygen-sensing transcription factor, promotes cell survival under hypoxic conditions, including the early pre-angiogenic period of tumorigenesis, and is known to contribute to many malignancies. However HIF-1α can also be activated by inflammatory mediators, and can activate inflammation-modulating proteins itself, including heme oxygenase-1 (HO-1) and the cytokine IL-6. Recently HIF-1α was reported to be induced by UVB (290-320 nm) radiation in cultured human keratinocytes, acting as a stress protein associated with the release of reactive oxygen species. In this in vivo murine study we demonstrate that HIF-1α protein is an early responder to UV radiation in the skin, and its activation can be attenuated by treating mice with its post-translational inhibitor, YC-1. Treatment with YC-1 following UV-irradiation of mice has revealed the involvement of HIF-1α in UV-induced inflammation, IL-6 production, and epidermal hyperplasia. In addition, upregulated cutaneous HIF-1α was found to be an important factor in the UV-suppression of T cell-mediated immunity, measured by contact hypersensitivity (CHS). The mechanism remains unclear, however it did not appear to involve the immunosuppressive cutaneous photoproduct cis-urocanic acid, but HIF-1α induction was inhibited by irradiation with photoimmune protective UVA (320-400 nm), implicating a negative correlation between the two stress proteins, HIF-1α and the photoimmune protective UVA responder HO-1.


Subject(s)
Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Immune Tolerance/radiation effects , Skin/pathology , Skin/radiation effects , Ultraviolet Rays/adverse effects , Animals , Dermatitis, Contact/etiology , Dermatitis, Contact/immunology , Dermatitis, Contact/metabolism , Edema/drug therapy , Edema/etiology , Edema/immunology , Edema/metabolism , Female , Gene Expression Regulation/radiation effects , Hyperplasia/etiology , Hyperplasia/immunology , Hyperplasia/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Indazoles/pharmacology , Indazoles/therapeutic use , Inflammation/etiology , Inflammation/immunology , Inflammation/metabolism , Interleukin-6/metabolism , Mice , Mice, Inbred C57BL , Skin/immunology , Skin/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/radiation effects
4.
Photochem Photobiol Sci ; 9(4): 601-7, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20354657

ABSTRACT

The goji berry, Lycium barbarum, has long been recognised in traditional Chinese medicine for various therapeutic properties based on its antioxidant and immune-modulating effects. This study describes the potential for orally consumed goji berry juice to alter the photodamage induced in the skin of mice by acute solar simulated UV (SSUV) irradiation. In Skh:hr-1 hairless mice, 5% goji berry juice significantly reduced the inflammatory oedema of the sunburn reaction. Dilutions of goji berry juice between 1% and 10% dose-dependently protected against SSUV-induced immunosuppression, and against suppression induced by the mediator, cis-urocanic acid, measured by the contact hypersensitivity reaction. The immune protection could not be ascribed to either the minor excipients in the goji juice, pear and apple juice, nor the vitamin C content, nor the preservative, and appeared to be a property of the goji berry itself. Antioxidant activity in the skin was demonstrated by the significant protection by 5% goji juice against lipid peroxidation induced by UVA radiation. Furthermore, two known inducible endogenous skin antioxidants, haem oxygenase-1 and metallothionein, were found to be involved in the photoimmune protection. The results suggest that consumption of this juice could provide additional photoprotection for susceptible humans.


Subject(s)
Antioxidants/pharmacology , Beverages , Drinking , Lycium/chemistry , Radiation Injuries, Experimental/prevention & control , Skin Diseases/prevention & control , Ultraviolet Rays/adverse effects , Animals , Antioxidants/therapeutic use , Edema/complications , Edema/diet therapy , Edema/immunology , Female , Heme Oxygenase-1/metabolism , Hypersensitivity/immunology , Immunosuppression Therapy , Inflammation/complications , Inflammation/diet therapy , Inflammation/immunology , Lipid Peroxidation/drug effects , Lipid Peroxidation/radiation effects , Metallothionein/metabolism , Mice , Mice, Hairless , Oleic Acids/immunology , Oxidative Stress/drug effects , Oxidative Stress/radiation effects , Radiation Injuries, Experimental/immunology , Radiation Injuries, Experimental/metabolism , Skin Diseases/etiology , Skin Diseases/immunology , Skin Diseases/metabolism , Sunburn/complications , Sunburn/diet therapy , Sunburn/immunology
5.
Photochem Photobiol Sci ; 9(4): 608-14, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20354658

ABSTRACT

We have reported previously that a deficiency in signalling by the non-classical oestrogen receptor-beta (Er-beta) exacerbates immunosuppression by UV radiation in the mouse. Because photoimmune suppression is a risk factor for skin cancer development, we hypothesize that Er-beta deficiency will promote skin tumour growth. Therefore we have blocked Er signalling pharmacologically in the Skh:hr-1 hairless mouse by topical treatments with the Er antagonist ICI 182,780, and genetically in haired mice by using the specific Er-beta knockout mouse (targeted mutation of the Er-beta), and examined the growth rate of 3 transplantable skin tumour cell lines in their syngeneic host mice. Two UV-induced squamous cell carcinoma (SCC) cell lines transplanted into the Skh:hr-1 recipients were found to have regressor qualities that were delayed by prior immunosuppressive solar-simulated UV (SSUV) irradiation. For the T79 SCC, regression was significantly further delayed by combined pretreatment with SSUV+ICI 182,780, and the diameters of the surviving tumours were slightly larger. For the KL3.0 SCC, both SSUV and combined SSUV+ICI 182,780 pretreatments completely inhibited tumour regression, and resulted in significantly greater tumour diameters than in unirradiated recipient mice. In heterozygous Er-beta deficient mice (Er-beta+/-), the B16/F10 melanoma grew progressively and significantly faster than in the wild type control mice (C57BL/6), and growth rate was accelerated by prior SSUV irradiation. Homozygous Er-beta-/- mice supported the most rapid B16/F10 growth that was further accelerated by prior SSUV irradiation. Therefore Er signalling, specifically by Er-beta, has a natural endogenous protective role against skin tumour growth, probably mediated via immunological pathways.


Subject(s)
Estrogen Receptor beta/metabolism , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Animals , Cell Line, Tumor , Cell Proliferation , Cell Transformation, Neoplastic , Dermatitis, Contact/immunology , Dermatitis, Contact/metabolism , Estradiol/analogs & derivatives , Estradiol/pharmacology , Estrogen Receptor beta/deficiency , Estrogen Receptor beta/genetics , Female , Fulvestrant , Gene Knockout Techniques , Humans , Mice , Neoplasm Transplantation , Skin Neoplasms/immunology , Ultraviolet Rays/adverse effects
6.
Immunol Cell Biol ; 88(7): 727-33, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20212509

ABSTRACT

The antioxidant and anti-proliferative biological effects of isoflavonoids are relevant properties to counteract the characteristics of many cutaneous diseases. This study uses ultraviolet (UV)B irradiation to induce inflammation in the mouse skin, as a model for some symptoms of cutaneous inflammatory and hyperproliferative diseases such as psoriasis in humans, with the objective of testing two topically applied isoflavonoid compounds for therapeutic properties. UVB exposure resulted in the overexpression of the cytokines, tumour necrosis factor (TNF)-α, interleukin (IL)-6 and the adhesion molecule P-cadherin. Infiltration into the dermal compartment of mast cell populations was also induced. These factors are also overexpressed in psoriatic skin. The effect of topical applications of two isoflavonoids, equol and a synthetic analogue NV-38, was tested. Both isoflavonoids dose dependently inhibited the UVB induction of cutaneous TNF-α mRNA and protein, a cytokine critical for the initiation of psoriatic inflammation. Expression of IL-6 mRNA and protein was also decreased, and the number of infiltrating mast cells into the dermis was reduced by both isoflavonoids. Furthermore, the upregulated mRNA and protein levels of P-cadherin, a marker characteristic of cutaneous hyperproliferation, were also normalized by both isoflavonoids. These results suggest that this class of compounds has the potential for useful, innocuous anti-inflammatory therapy from topical application in human cutaneous diseases.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Cadherins/radiation effects , Dermatitis/drug therapy , Isoflavones/pharmacology , Skin/drug effects , Administration, Cutaneous , Animals , Cadherins/antagonists & inhibitors , Cadherins/metabolism , Equol , Humans , Interleukin-6/antagonists & inhibitors , Interleukin-6/metabolism , Isoflavones/therapeutic use , Mast Cells , Mice , Mice, Hairless , Mice, Inbred C3H , Mice, Inbred C57BL , Models, Animal , Psoriasis/drug therapy , Skin/pathology , Skin/radiation effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism , Ultraviolet Rays , Up-Regulation/drug effects , Up-Regulation/radiation effects
7.
J Invest Dermatol ; 129(11): 2702-10, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19474803

ABSTRACT

Previous studies have found that signaling by the estrogen receptor-beta (Er-beta) attenuated solar-simulated UV radiation (SSUV)-induced immunosuppression. This study seeks evidence for a common mechanism for this immunoprotection for both Er-beta signaling and irradiation with the UVA waveband. In Skh:hr-1 hairless mice, the immunoprotection afforded by UVA exposure against subsequent UVB or cis-urocanic acid suppression of contact hypersensitivity (CHS) was abrogated by treatment with the antiestrogen, ICI 182,780. Furthermore, in normal C57BL mice, UVA enrichment of UVA/UVB sources provided protection against UVB-suppressed CHS and upregulated epidermal IL-10 expression, but this protection was inhibited in Er-beta-/- mice. These observations indicated that the immunoprotective response to UVA was dependent on Er-beta signaling. As earlier studies have established that UVA photoimmune protection depends on the induction of the stress enzyme, heme oxygenase (HO)-1, its activity was examined relative to Er-beta. Immunoprotection against SSUV by 17-beta-estradiol was prevented by inhibiting HO enzyme activity; immunoprotection against cis-urocanic acid by carbon monoxide (HO product) was prevented by ICI 182,780. In addition, the HO-1 gene was unresponsive to UVA induction in Er-beta-/- mice. Therefore, HO-1 inducibility and Er-beta signaling are interdependent requisite responses to the UVA waveband for its immunoprotective action against UVB exposure.


Subject(s)
Estrogen Receptor beta/genetics , Heme Oxygenase-1/genetics , Immune Tolerance/radiation effects , Signal Transduction/radiation effects , Ultraviolet Rays , Animals , Enzyme Inhibitors/pharmacology , Epidermis/immunology , Epidermis/pathology , Epidermis/radiation effects , Estradiol/analogs & derivatives , Estradiol/pharmacology , Estrogen Antagonists/pharmacology , Estrogen Receptor beta/antagonists & inhibitors , Estrogen Receptor beta/metabolism , Female , Fulvestrant , Heme Oxygenase-1/antagonists & inhibitors , Heme Oxygenase-1/metabolism , Immune Tolerance/immunology , Interleukin-10/metabolism , Metalloporphyrins/pharmacology , Mice , Mice, Hairless , Mice, Inbred C57BL , Mice, Mutant Strains , Protoporphyrins/pharmacology , RNA, Messenger/metabolism , Signal Transduction/immunology , Urocanic Acid/pharmacology
8.
J Invest Dermatol ; 129(6): 1539-46, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19110542

ABSTRACT

The proinflammatory cytokine IL-6 is released in the skin following UVB irradiation, but its potential for photoimmune modulation remains unclear. This study utilizes IL-6-deficient mice to demonstrate that IL-6 does not contribute to the normal contact hypersensitivity response, nor to its systemic suppression by UVB radiation or cis-urocanic acid. In contrast, IL-6 was required for the attenuation of UVB- or cis-urocanic acid-induced immunosuppression by sequential or concomitant UVA irradiation. The IL-6 was essential for several reactions previously established to be relevant for UVA photoimmune protection, namely the induction of heme oxygenase-1 (HO-1), the activity of its product carbon monoxide in activating guanylyl cyclase, and the consequent elevation of cutaneous cyclic guanosine monophosphate concentration. In addition, IL-6-deficient mouse skin had an elevated constitutive overexpression of HO activity, apparently not associated with photoimmune protection. This suggested that both the cutaneous level of HO activity, and the receptiveness of the HO-1 gene to stressors like UVA, normally controlled by promoter-binding repressor proteins, may also be under IL-6 control. Thus IL-6 has an important photoimmune protective function through interaction at several levels in the pathway determining the immunologically advantageous actions of UVA radiation. This may constitute a valuable endogenous antiphotocarcinogenic regulatory mechanism.


Subject(s)
Immune System/radiation effects , Interleukin-6/physiology , Ultraviolet Rays , Animals , Carbon Monoxide/chemistry , Carbon Monoxide/metabolism , Cyclic GMP/metabolism , Female , Heme Oxygenase (Decyclizing)/metabolism , Heme Oxygenase-1/metabolism , Immunosuppressive Agents/pharmacology , Interleukin-6/genetics , Interleukin-6/metabolism , Light , Mice , Mice, Inbred C57BL , Models, Biological , Promoter Regions, Genetic
9.
Photochem Photobiol Sci ; 7(1): 120-5, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18167605

ABSTRACT

A previous study in the hairless mouse, in which the photoimmune protective properties of a topical phytoestrogen or 17-beta-estradiol were abrogated by the estrogen receptor antagonist ICI 182,780, revealed that estrogen receptor (Er) signaling is involved in the regulation of the suppression of immune function by UVB (290-320 nm) radiation. Here we identify the expression of Er-beta but not Er-alpha mRNA in hairless mouse skin, whereas Er-alpha and Er-beta mRNA were present in normal haired mouse skin. This suggests that the non-classical estrogen target Er-beta is involved in the photoimmune modulation, and is consistent with Er-alpha being more closely associated with hair growth control, as indicated by other studies. In mice with a null mutation for Er-beta, there was a significant exacerbation of the solar simulated UV (290-400 nm)-induced suppression of contact hypersensitivity. Immunohistochemical analysis revealed that the Er-beta deficiency inhibited the normally immunoprotective upregulation by the UVA (320-400 nm) waveband of the epidermal expression of the cytokines IFN-gamma and IL-12. Er-beta deficiency also significantly increased the UVB-induced expression of the immunosuppressive cytokine IL-10. Thus Er signalling via the Er-beta is evidently a major regulator of the UVA and UVB waveband interactions that determine the skin's immune functional status, and achieves this by normalization of the cutaneous cytokine array in the UV-irradiated skin.


Subject(s)
Cytokines/immunology , Cytokines/metabolism , Epidermis/metabolism , Epidermis/radiation effects , Estrogen Receptor beta/metabolism , Signal Transduction/immunology , Signal Transduction/radiation effects , Animals , Dermatitis, Contact , Epidermis/immunology , Estrogen Receptor beta/deficiency , Estrogen Receptor beta/genetics , Female , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxazolone/pharmacology , RNA, Messenger/genetics , Ultraviolet Rays
10.
J Invest Dermatol ; 127(9): 2236-44, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17476293

ABSTRACT

UV radiation-induced epidermal apoptotic sunburn cells provide a mechanism for eliminating cells with irreparable DNA damage. The UVB (290-320 nm) waveband is mainly responsible, but the role of UVA (320-400 nm) is less clear, and possible waveband interactions have not been examined. Recent studies in mice reveal a protective role for UVA against UVB-induced inflammation and immunosuppression, mediated via cutaneous heme oxygenase (HO). As HO has antiapoptotic properties in other tissues, this study examines the effect of UVA/UVB waveband interaction on apoptosis in the Skh:hr-1 hairless mouse epidermis. Apoptosis was assessed by sunburn cell number, caspase-3-positive cell number, and degree of DNA fragmentation, in mice exposed to radiation sources providing a constant UVB dose with increasing proportions of UVA. The results indicated that as the UVA/UVB ratio was increased, both the sunburn cell and caspase-3-positive cell number decreased, and the degree of DNA fragmentation was reduced. Treatment of mice with the HO inhibitor, tin protoporphyrin-IX, markedly reduced the UVA antiapoptotic effect, confirming a major role for HO. The observations suggest that UVA reduces UVB-induced DNA damage, and may therefore have anti-photocarcinogenic properties that could be harnessed for better photoprotection in humans.


Subject(s)
Apoptosis , Skin/metabolism , Skin/radiation effects , Animals , Carcinogens/chemistry , Caspase 3/metabolism , DNA Damage , DNA Fragmentation , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Epidermis/metabolism , Female , Heme Oxygenase (Decyclizing)/metabolism , Mice , Sunburn , Ultraviolet Rays
11.
Cancer Immunol Immunother ; 56(11): 1807-15, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17440721

ABSTRACT

Exposure of the skin of mice to UVA (320-400 nm) radiation has been shown to provide protection against the immunosuppressive effects of UVB (290-320 nm) radiation. The UVA protection was mediated via the UVA induction of the stress protein heme oxygenase-1, and its enzymatic product carbon monoxide (CO). Because UVB-induced immunosuppression is an accompanying and prerequisite feature of the promotion phase of photocarcinogenesis, the potential for immunoprotective CO to act as an anti-skin cancer agent was tested in this study. Groups of female albino Skh:hr-1 hairless mice were irradiated chronically with daily minimally erythemogenic doses of solar simulated UV radiation (SSUV) during a 10 week-period to induce photocarcinogenesis. The effect of repeated topical application of lotions containing a CO-releasing molecule (CORM-2; tricarbonyldichlororuthenium (II) dimer) at 250 or 500 microM, that had previously been shown in short-term experiments to provide photoimmune protection in mice, was measured. Tumor development was monitored for 29 weeks. Topical CORM-2 treatment was observed to reduce the acute and chronic inflammatory erythema reaction compared with control irradiated mice that did not receive CORM-2 lotions, and to reduce the chronic epidermal hyperplasia accompanying tumor outgrowth. The CORM-2 treatments provided a significant moderate inhibition of early tumor appearance dose-dependently, significantly reduced the average tumor multiplicity, increased the regression of established tumors dose-dependently, and inhibited the formation of large locally invasive tumors. The CORM-2 treatments also reduced the expression of immunosuppressive IL-10 in the uninvolved epidermis and dermis of tumor-bearing mice, and enhanced immunopotentiating epidermal IL-12 expression. Therefore CO signalling was revealed to have previously unrecognized anti-carcinogenic functions in the skin, consistent with a protective modulation of the epidermal cytokines. This is a novel observation that also implies that the UVA waveband that produces CO physiologically in exposed skin, might likewise be found to have an anti-photocarcinogenic action.


Subject(s)
Carbon Monoxide/physiology , Carcinogens/radiation effects , Skin Neoplasms/prevention & control , Ultraviolet Rays , Animals , Carbon Monoxide/metabolism , Disease Progression , Down-Regulation , Female , Heme Oxygenase-1/metabolism , Immunohistochemistry , Interleukin-10/metabolism , Interleukin-2/metabolism , Mice , Mice, Hairless , Signal Transduction/physiology , Skin Neoplasms/physiopathology , Tumor Burden
12.
J Invest Dermatol ; 126(1): 191-7, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16417236

ABSTRACT

The immunomodulating properties of UVA radiation remain controversial. Here, we demonstrate in female inbred Skh:hr-1 mice that single subinflammatory UVA exposures between 1.61 and 580.5 kJ/m(2) are not immunosuppressive. Furthermore, UVA exposures between 16.13 and 580.5 kJ/m(2) provided dose-related immunoprotection against UVB-induced immunosuppression. Higher UVA exposures (870.8-1,161 kJ/m(2)) became inflammatory and immunosuppressive alone, and lost the photoimmunoprotective capacity. We previously reported that UVA photoimmunoprotection depends on the induction of cutaneous heme oxygenase-1, particularly its enzymatic product, carbon monoxide (CO). CO was suggested to activate cutaneous guanylyl cyclase (GC), as the specific GC inhibitor, 1H-(1,2,4)oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ), abrogated CO photoimmunoprotection in the mouse. This study shows that cutaneous cyclic guanosine monophosphate (cGMP) concentration increased only following immunoprotective UVA doses, or immunoprotective topical CO treatment, and cGMP production was inhibited by ODQ. Conversely, cGMP concentration was increased by inhibition of its degradative phosphodiesterase (PDE) with topical sildenafil. The PDE-5 isoform was identified in normal mouse skin. Subsequently, a moderate concentration of sildenafil was shown to simulate the effect of UVA in protecting against photoimmunosuppression by solar-simulated UV radiation or its mediator cis-urocanic acid. Thus, cutaneous cGMP, controlled by its synthesis via CO-activated GC and its degradation by PDE-5, is strongly associated with UVA photoimmunoprotection.


Subject(s)
Cyclic GMP/metabolism , Dermatitis, Contact/immunology , Immune Tolerance , Skin/radiation effects , Ultraviolet Rays , Animals , Carbon Monoxide/pharmacology , Cyclic GMP/analysis , Dermatitis, Contact/metabolism , Dose-Response Relationship, Radiation , Enzyme Activation , Female , Guanylate Cyclase/antagonists & inhibitors , Guanylate Cyclase/metabolism , Immune Tolerance/drug effects , Mice , Mice, Inbred Strains , Oxadiazoles/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/drug effects , Piperazines/pharmacology , Purines , Quinoxalines/pharmacology , Sildenafil Citrate , Skin/immunology , Skin/metabolism , Sulfones
13.
J Invest Dermatol ; 126(1): 198-204, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16417237

ABSTRACT

Previous studies report that selected topical isoflavonoids are immunoprotective in both mice and humans, when applied following UV irradiation. Isoflavonoids have documented antioxidant activity, but their mechanism of immunomodulation remains unclear. This study examines whether photoimmunoprotection by the isoflavonoids might result from their interaction with one cutaneous antioxidant known to modulate UV photodamage, metallothionein (MT). In mice bearing a null mutation for MT-I and -II, we found that immunoprotection by the isoflavonoid 4',7-dihydroxyisoflavane (equol) against solar-simulated UV radiation (SSUV) or exogenous cis-urocanic acid was abrogated. Topical equol did not activate MT expression in normal mouse skin, but markedly enhanced the increase in MT expression in murine epidermis following SSUV irradiation. Normal human skin, unlike murine, expressed MT in the basal epidermis. Following SSUV irradiation, topical application of the related synthetic isoflavonoid NV-07alpha to human skin also markedly enhanced epidermal MT expression. The NV-07alpha has been reported previously to protect humans against the UV suppression of Mantoux reactions. Thus, epidermal MT expression appears to protect against photoimmunosuppression in both human and mouse skin. We speculate that equol and its related derivative NV-07alpha may activate the MT gene synergistically with SSUV, to produce the enhanced immunoprotective effect.


Subject(s)
Dermatitis, Contact/immunology , Immune Tolerance/drug effects , Isoflavones/administration & dosage , Metallothionein/metabolism , Skin/drug effects , Skin/radiation effects , Ultraviolet Rays , Animals , Dermatitis, Contact/metabolism , Equol , Humans , Isoflavones/pharmacology , Metallothionein/analysis , Metallothionein/genetics , Mice , Mice, Mutant Strains , RNA, Messenger/analysis , RNA, Messenger/metabolism , Skin/chemistry , Skin/metabolism
14.
J Invest Dermatol ; 124(3): 644-50, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15737207

ABSTRACT

Accumulating evidence suggests that suberythemogenic ultraviolet A (UVA) (320-400 nm) exposure protects against the immunosuppressive effect of ultraviolet B (290-320 nm) radiation or its epidermal photoproduct, cis-urocanic acid (cis-UCA). In skin, UVA photoimmunoprotection is mediated by the inducible antioxidant stress enzyme, heme oxygenase-1 (HO-1), which degrades heme into carbon monoxide (CO), iron, and biliverdin (reduced to bilirubin), and is important for cell survival under conditions of oxidative stress. The identity of the HO enzymatic product(s) that provide the immunoprotection is unknown. Here we examine the potential of CO to fulfill this role in hairless mouse skin, utilizing a novel CO-releasing molecule (CO-RM) to deliver CO to the skin topically. The CO-RM released CO gradually from the lotion vehicle during 3 h following its preparation, and between 50 and 500 microM, concentration-dependently protected mice against the suppression of contact hypersensitivity by either solar-simulated UV radiation (SSUVR) or cis-UCA, whereas aged CO-depleted CO-RM was inactive. Thus, the CO-RM treatment mimicked UVA-photoimmunoprotection, and identified HO-released CO as the protective mediator, providing evidence that the murine cutaneous immune system is modulated by this gaseous messenger. Preliminary evidence for involvement of guanylyl cyclase was obtained by treatment of the mouse with its specific inhibitor 1H-(1,2,4)oxadiazolo-(4,3-1)quinoxaline-1-one, which abrogated UVA photoimmunoprotection.


Subject(s)
Carbon Monoxide/metabolism , Dermatitis, Contact/immunology , Dermatitis, Contact/metabolism , Immune Tolerance/radiation effects , Ultraviolet Rays , Animals , Enzyme Inhibitors/pharmacology , Female , Guanylate Cyclase/antagonists & inhibitors , Guanylate Cyclase/metabolism , Heme Oxygenase (Decyclizing)/metabolism , Mice , Mice, Hairless , Organometallic Compounds/pharmacology , Skin/immunology , Skin/metabolism , Skin/radiation effects , Urocanic Acid/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolism
15.
J Invest Dermatol ; 122(4): 1030-6, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15102094

ABSTRACT

The induction of heme oxygenase-1 (HO-1) by ultraviolet A (UVA) (320-400 nm) radiation provides a protective cellular defence against oxidative stress, and has been well demonstrated in cultured human skin fibroblasts, although keratinocytes were unreactive. The UVA responsiveness of HO-1 however, has not been confirmed in intact skin. Previously, we reported that UVA-inducible HO enzyme activity in mouse skin is protective against UVB-induced immunosuppression. This study identifies the induced HO isoform and its localization in mouse skin irradiated in vivo with such an immunoprotective UVA dose. We found that HO-1 mRNA was expressed in UVA-irradiated skin, but not in normal or UVB-irradiated skin, whereas constitutive HO-2 was always present. UVA-irradiated skin had increased HO enzyme activity and bilirubin content, and decreased heme content, consistent with HO-1 induction. In situ hybridization and immunohistochemical staining localized HO-1 mRNA and protein to both epidermis and dermis, with strongest expression in basal keratinocytes and weaker expression in dermal fibroblast-like and other cells, in contrast with UVA-induced HO-1 in cultured human skin fibroblasts. This suggests that cultured skin cells may not fully represent skin functions in vivo, or that there may be inherent differences between human and hairless mouse skin HO-1 responses.


Subject(s)
Dermis/enzymology , Epidermis/enzymology , Heme Oxygenase (Decyclizing)/metabolism , Immune System/radiation effects , Ultraviolet Rays , Animals , Biomarkers/analysis , Dermis/radiation effects , Epidermis/radiation effects , Heme Oxygenase (Decyclizing)/genetics , Heme Oxygenase-1 , In Situ Hybridization , Male , Membrane Proteins , Mice , Mice, Hairless , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Up-Regulation
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