RESUMEN
Interleukin 35 (IL-35), a cytokine secreted by regulatory T (Treg) cells from the differentiation of conventional CD4+ T cells, is a member of the IL-12 family. The IL-12 family of cytokines exhibits an anti-inflammatory property. IL-35 has recently been shown to influence the immune modulation in various diseases, including inflammatory bowel disease, Graves' disease, rheumatoid arthritis, colitis, psoriasis, and type 1 diabetes (T1D). T1D is an immune-related disease caused by destruction of pancreatic ß cells, characterized by an absolute lack of insulin. Recently, studies have suggested that protective effects of IL-35 work by improving blood glucose levels and preventing an attack of inflammatory factors on the islets. The protective mechanism may be closely related to the anti-inflammatory properties of IL-35, which include regulating macrophage phenotype, suppressing T cell proliferation, decreasing the differentiation of Th17 cells, increasing the Treg cell population, and inducing IL-35-producing regulatory T cells (iTr35). Here, we review the protective effects and mechanisms of action of IL-35 in T1D.
RESUMEN
This is the first report, to our knowledge, of the use of dupilumab in treating eosinophilic fasciitis (EF). Our case supports that Type 2 innate immunity might be related to EF and that T helper 2 cytokines play important roles in EF.
Asunto(s)
Eosinofilia , Fascitis , Humanos , Fascitis/tratamiento farmacológico , Eosinofilia/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéuticoRESUMEN
Dermoscopy is an efficient and non-invasive technique which has been widely used in the diagnosis of nail disorders including nail psoriasis (NP). Many nail dermoscopic features are considered as clues to NP. The aim of this study was to investigate specific dermoscopic features of fingernail psoriasis and the correlation between the severity of nail lesions or systemic inflammation, and psoriasis severity of skin and nail. This observational study recruited 135 patients with fingernail psoriasis (1186 fingernails) and 30 patients with onychomycosis (80 fingernails). All of the involved fingernails were examined with a handheld dermatoscope. The Nail Psoriasis Severity Index score (NAPSI) score, Psoriasis Area and Severity Index (PASI) score, body surface area (BSA), and detailed history of patients with psoriasis were recorded. Mann-Whitney U-test, χ2 -test, Spearman's correlation, and Kruskal-Wallis H-test were used for statistical analysis, and the significance threshold was p < 0.05. The trial registration number was 2020-SR-045. We identified onycholysis as the most common feature (93.3%) of fingernail psoriasis. Red lunula, longitudinal fissures, transverse grooves, nail plate crumbling, trachyonychia, oil-dropping sign, erythematous border of an onycholytic area, subungual hyperkeratosis, and dilated streaky capillaries were relevant to NP severity (p < 0.05). Red lunula, transverse grooves, nail plate crumbling, trachyonychia, oil-dropping sign, erythematous border of an onycholytic area, splinter hemorrhages, and dilated streaky capillaries were relevant to systemic inflammation severity (p < 0.05). The total NAPSI score was positively associated with the PASI score and BSA (p < 0.0001). The thumb had a higher NAPSI score than the other fingers (p < 0.05). In conclusion, dermoscopic features can improve the accuracy of diagnosis of nail psoriasis, and have correlations with psoriasis severity.
Asunto(s)
Enfermedades de la Uña , Onicomicosis , Psoriasis , Humanos , Enfermedades de la Uña/diagnóstico por imagen , Uñas/diagnóstico por imagen , Psoriasis/diagnóstico por imagen , Índice de Severidad de la EnfermedadRESUMEN
This study reports a case of an 80-year-old male who suffered from drug eruption due to oral allopurinol for the treatment of gout. This patient complained of widespread erythema and maculopapule with itch, and small quantities of purplish-red rash with diffused distribution on four limbs were noted. After he was hospitalized, the area with purpuric rash increased in size, and hypofibrinogenemia was found. After treatment with intravenous infusion of fibrinogen and cryoprecipitate, and continued treatment with high-dose methylprednisolone, the skin rash gradually went away. This is the first report of purpura and hypofibrinogenemia induced by allopurinol and the pathophysiology underlying this reaction remained unknown.
Asunto(s)
Afibrinogenemia/tratamiento farmacológico , Alopurinol/efectos adversos , Administración Oral , Afibrinogenemia/patología , Anciano de 80 o más Años , Alopurinol/administración & dosificación , Erupciones por Medicamentos , Fibrinógeno/administración & dosificación , Humanos , Infusiones Intravenosas , Masculino , Metilprednisolona/administración & dosificaciónRESUMEN
Panax notoginseng saponins (PNS) are a patented product in the People's Republic of China, and have extensive effects on the cardiovascular system. Here we report on four elderly patients (one male and three female) with drug eruption induced by PNS injection. All developed a sudden skin rash with pruritus from head to foot, and subsequently accepted hospitalization. In each case, PNS had been used for less than 1 week before appearance of the rash. No specific short-term medications or changes in diet or exposure to environmental factors immediately prior to appearance of the rash were identified. These four patients had some interesting features in common, ie, pustules, fever, and elevated circulating neutrophil counts, which required high-dose, long-term glucocorticoid therapy. To our knowledge, this is the first report of pustular drug eruption induced by PNS and provides a useful reference and warning for clinicians.
Asunto(s)
Erupciones por Medicamentos/etiología , Medicamentos Herbarios Chinos/efectos adversos , Panax notoginseng/química , Saponinas/efectos adversos , Anciano , Anciano de 80 o más Años , Erupciones por Medicamentos/tratamiento farmacológico , Erupciones por Medicamentos/patología , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Saponinas/aislamiento & purificaciónRESUMEN
BACKGROUND: The exposure of skin keratinocytes to Ultraviolet (UV) irradiation leads to Akt phosphorylation at Ser-473, which is important for the carcinogenic effects of excessive sun exposure. The present study investigated the underlying mechanism of Akt Ser-473 phosphorylation by UVB radiation. RESULTS: We found that DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and mammalian target of rapamycin (mTOR) complex 2 (mTORC2) were both required for UVB-induced Akt Ser-473 phosphorylation in keratinocytes. Inhibition of DNA-PKcs activity via its inhibitor NU7026, a dominant-negative kinase-dead mutation, RNA interference (RNAi) or gene depletion led to the attenuation of UVB-induced Akt Ser-473 phosphorylation. Meanwhile, siRNA silencing or gene depletion of SIN1, a key component of mTORC2, abolished Akt Ser-473 phosphorylation by UVB. Significantly, we discovered that DNA-PKcs was associated with SIN1 in cytosol upon UVB radiation, and this complexation appeared required for Akt Ser-473 phosphorylation. Meanwhile, this DNA-PKcs-SIN1 complexation by UVB was dependent on epidermal growth factor receptor (EGFR) activation, and was disrupted by an EGFR inhibitor (AG1478) or by EGFR depletion. UVB-induced complexation between DNA-PKcs and mTORC2 components was also abolished by NU7026 and DNA-PKcs mutation. Finally, we found that both DNA-PKcs and SIN1 were associated with apoptosis resistance of UVB radiation, and inhibition of them by NU7026 or genetic depletion significantly enhanced UVB-induced cell death and apoptosis. CONCLUSION: Taken together, these results strongly suggest that DNA-PKcs-mTORC2 association is required for UVB-induced Akt Ser-473 phosphorylation and cell survival, and might be important for tumor cell transformation.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteína Quinasa Activada por ADN/metabolismo , Queratinocitos/enzimología , Proteínas Nucleares/metabolismo , Procesamiento Proteico-Postraduccional/efectos de la radiación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Rayos Ultravioleta , Animales , Apoptosis/efectos de la radiación , Línea Celular Transformada , Supervivencia Celular/efectos de la radiación , Cromonas/farmacología , Proteína Quinasa Activada por ADN/antagonistas & inhibidores , Activación Enzimática , Receptores ErbB/metabolismo , Humanos , Queratinocitos/fisiología , Queratinocitos/efectos de la radiación , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , Ratones , Morfolinas/farmacología , Complejos Multiproteicos/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Fosforilación , Cultivo Primario de Células , Tolerancia a Radiación , Piel/patología , Neoplasias Cutáneas/enzimología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
We demonstrate here that a relative low dose of perifosine significantly enhanced UVB-induced apoptosis in skin cells (keratinocytes and fibroblasts), associated with a significant increase of reactive oxygen species (ROS) and ceramide production as well as multiple perturbations of diverse cell signaling pathways, shifting to a significant pro-apoptosis outcomes. Perifosine inhibited UVB-induced pro-survival Akt/mammalian target of rapamycin (mTOR) and ERK activation, while facilitating pro-apoptotic AMP-activated protein kinas (AMPK), c-Jun-NH(2)-kinase (JNK), and p53 activation; these signaling changes together promoted a striking increase in skin cell apoptosis and a significantly reduced amount of DNA damages. Our results suggest that perifosine may represent a novel skin cancer prevention strategy.
Asunto(s)
Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Fosforilcolina/análogos & derivados , Neoplasias Cutáneas/prevención & control , Piel/citología , Piel/efectos de los fármacos , Rayos Ultravioleta , Células Cultivadas , Ceramidas/biosíntesis , Relación Dosis-Respuesta a Droga , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Fosforilcolina/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The aim of the current study is to investigate the effect of ceramides on genistein-induced anti-melanoma effects in vitro. We found that exogenously added cell-permeable short-chain ceramides (C6) dramatically enhanced genistein-induced growth inhibition and apoptosis in cultured melanoma cells. Genistein treatment only induced a moderate intracellular ceramides accumulation in B16 melanoma cells. Two different agents including 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), a ceramide glucosylation inhibitor, and the sphingosine kinase-1 (SphK1) inhibitor II (SKI-II), a sphingosine (ceramides precursor) phosphorylation inhibitor, both facilitated genistein-induced ceramides accumulation and melanoma cell apoptosis. Co-administration of ceramide (C6) and genistein induced a significant Akt inhibition and c-jun-NH(2)-kinase (JNK) activation, caspase-3 cleavage and cytochrome c release. Caspase-3 inhibitor z-DVED-fmk, JNK inhibitor SP 600125, or to restore Akt activation by introducing a constitutively active form of Akt (CA-Akt) diminished ceramide (C6) and genistein co-administration-induced in vitro anti-melanoma effect. Our study suggests that increasing cellular level of ceramides may sensitize genistein-induced anti-melanoma effects.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ceramidas/farmacología , Resistencia a Antineoplásicos , Genisteína/farmacología , Melanoma/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ceramidas/biosíntesis , Activación Enzimática , Humanos , MAP Quinasa Quinasa 4/biosíntesis , Melanoma Experimental/patología , Ratones , Morfolinas/farmacología , TiazolesRESUMEN
Solar ultraviolet (UV) irradiation is one of the most significant extrinsic factors contributing to skin photoaging. One major characteristic of photoaging induced by UV is water loss of the skin. Water movement across the plasma membrane can occur via two pathways: by diffusion through the lipid bilayer and by membrane-inserted water channels (aquaporins). In this study we demonstrate that UV induces aquaporin-3 (AQP3) downregulation in cultured keratinocytes (HaCaT cells). PD98059 and U0126, MEK/ERK inhibitors, inhibit UV-induced AQP3 loss. Trans-Zeatin (tZ), which alone induces AQP3 expression, attenuates UV-induced loss of AQP3. We found that tZ inhibits UV-induced MEK/ERK activation; the latter serves as the key signal pathway mediating UV-induced AQP3 loss. Using specific AQP3 siRNA knockdown, we found AQP3 is involved in wound healing in human skin keratinocytes. Loss-of-AQP3-mediated delayed wound healing in UV-radiated skin keratinocytes is attenuated by tZ pretreatment. tZ pretreatment also attenuates UV-induced decreased water permeability in HaCaT cells. We concluded that UV radiation downregulates AQP3 in HaCaT cells. MEK/ERK activation is involved in this process. tZ treatment attenuates UV-induced AQP3 loss, in vitro wound healing delay and water permeability decrease. This work provides a new explanation for the anti-photoaging potential of tZ.
Asunto(s)
Acuaporina 3 , Regulación hacia Abajo , Queratinocitos/metabolismo , Rayos Ultravioleta , Zeatina , Acuaporina 3/genética , Acuaporina 3/metabolismo , Línea Celular , Permeabilidad de la Membrana Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de la radiación , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/efectos de la radiación , Inhibidores Enzimáticos/farmacología , Humanos , Imidazoles/farmacología , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Piridinas/farmacología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Agua/metabolismo , Cicatrización de Heridas/efectos de los fármacos , Cicatrización de Heridas/efectos de la radiación , Zeatina/química , Zeatina/farmacologíaRESUMEN
Chronic exposure to solar ultraviolet radiation (UV) induces photoaging, and ultimately photocarcinogenesis. Senescent human skin fibroblasts (HSFs) in UVB stress-induced premature senescence (UVB-SIPS) share a similar extracellular matrix (ECM) phenotype with other types of senescent fibroblast. ECM from senescent fibroblasts induced by a variety of stresses has been shown to promote preneoplastic and neoplastic epithelial cell growth, a potential mechanism in carcinogenesis. We undertook this study to explore whether the extracellular matrices from UVB-induced senescent fibroblasts have any effect on the proliferation of HaCaT cells. The results showed that ECM secreted from HSFs in UVB-SIPS has 13.15 and 29.27% more stimulatory effect on proliferation than ECM secreted from presenescent HSFs and non-ECM, respectively. ECM from fibroblasts in UVB-SIPS activates FAK, ERK, and AKT in HaCaT cells. ERK and PI3K/AKT inhibitors inhibit ECM-induced ERK, AKT activation and cell proliferation. Cytochalasin D, a destructive agent of the cytoskeleton, inhibits ECM-induced FAK activation and cell proliferation in HaCaT cells. Collectively, we conclude that ECM secreted from HSFs in UVB-SIPS promotes cell proliferation via ERK and PI3K/AKT pathways and modulation of FAK and cytoskeletal proteins in HaCaT cells. Pharmacological manipulation of those signaling components may lead to the prevention and treatment of skin cancer induced by chronic solar exposure.
Asunto(s)
Proliferación Celular , Matriz Extracelular/fisiología , Fibroblastos/efectos de la radiación , Rayos Ultravioleta , Apoptosis/efectos de los fármacos , Western Blotting , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Línea Celular , Transformación Celular Neoplásica/efectos de la radiación , Senescencia Celular/efectos de la radiación , Inhibidores Enzimáticos/farmacología , Matriz Extracelular/efectos de la radiación , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Citometría de Flujo , Quinasa 1 de Adhesión Focal/antagonistas & inhibidores , Quinasa 1 de Adhesión Focal/metabolismo , Humanos , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Piel/citología , Piel/metabolismo , Piel/efectos de la radiación , Envejecimiento de la Piel/efectos de la radiaciónRESUMEN
Chronic exposure to solar UV irradiation leads to photoaging, immunosuppression, and ultimately carcinogenesis. Cellular senescence is thought to play an important role in tumor suppression and apoptosis resistance. However, the relationships among stress-induced premature senescence (SIPS), tumorigenesis and apoptosis induced by UVB remain unknown. We developed a model of UVB-induced premature senescence in human skin fibroblasts (HSFs). After five repeated subcytotoxic UVB exposures at a dose of 10 mJ/cm2, the following biomarkers of senescence were markedly present: senescence-associated beta-galactosidase (SA beta-gal) activity, growth arrest, and the overexpression of senescence-associated genes. Firstly, there was an increase in the proportion of cells positive for SA beta-gal activity. Secondly, there was a loss of replicative potential as assessed by MTT assay. FACS analysis showed that UVB-stressed HSFs were blocked mostly in the G1 phase of the cell cycle, and replicative senescence, and protein expression of p53, p21(WAF-1) and p16(INK-4a) increased significantly. Thirdly, the mRNA levels of three senescence-associated genes, fibronectin, osteonectin and SM22, also increased. A real time PCR array to investigate the mRNA expression of p53-related genes involved in growth arrest, apoptosis and tumorigenesis indicated that p53, p21, p19, Hdm2, and Bax were up-regulated, and bcl, HIF-1alpha and VEGF were down-regulated. Collectively, our data suggest that UVB-induced SIPS plays an important role in p53-related apoptosis resistance and tumor suppression activity.
Asunto(s)
Apoptosis , Senescencia Celular , Fibroblastos/fisiología , Envejecimiento de la Piel , Proteína p53 Supresora de Tumor/metabolismo , Biomarcadores/metabolismo , Fibroblastos/citología , Fibroblastos/efectos de la radiación , Regulación de la Expresión Génica , Humanos , Datos de Secuencia Molecular , Estrés Oxidativo , Piel/citología , Piel/efectos de la radiación , Proteína p53 Supresora de Tumor/genética , Rayos UltravioletaRESUMEN
OBJECTIVE: To explore the effects of antisense epidermal growth factor receptor (EGF-R) oligodeoxynucleotides on ultraviolet-induced c-jun activity of keratinocytes after EGF-R oligodeoxynucleotides transfect to HaCaT in vitro. METHODS: c-jun DNA binding activity after ultraviolet-B (UVB) irradiation and EGF-R oligodeoxynucleotides transfection were determined with a highly sensitive and specific colorimetric method. After EGF-R oligodeoxynucleotides transfection, the mRNA level of EGF-R was detected by reverse transcription polymerase chain reaction method. RESULTS: Compared with control groups, c-jun activity increased significantly in UVB (10, 20, 30 mJ/cm2) irradiation groups (P < 0.05). EGF-R mRNA and c-jun activities induced by UVB were inhibited after the keratinocytes were transfected with EGF-R antisense oligodeoxynucleotides at 2, 4 and 8 microg/ml concentrations (P < 0.01). CONCLUSION: The ultraviolet-induced c-jun activity of keratinocytes can be mediated by EGF-R and inhibited by EGF-R antisense oligodeoxynucleotides, which is transfected to keratinocytes and mediated by lipofectamine.
Asunto(s)
Receptores ErbB/genética , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/efectos de la radiación , Oligodesoxirribonucleótidos Antisentido/farmacología , Línea Celular , Receptores ErbB/biosíntesis , Humanos , Queratinocitos/metabolismo , Transfección , Rayos UltravioletaRESUMEN
Ultraviolet (UV) radiation from the sun is widely considered as a major cause of human skin photoaging and skin cancer. UV radiation-induced proinflammatory cytokines mediated by NF-kappaB reportedly play important roles in photoaging and cancer. NF-kappaB and cytokines have been thus perceived as molecular targets for pharmacological intervention. With an increasing amount of knowledge of the actions of green tea extracts at cellular and molecular levels, the beneficial effect of drinking green tea has become well recognized if not completely accepted. The components in green tea have even been added to skin-care products unregulated, while the molecular mechanisms of the actions of those components on human skin are being unraveled. Using cultured human keratinocytes, we investigated the effects of (-)-epigallocatechin-3-gallate (EGCG), a major polyphenolic constituent in green tea, on UV-induced activation of transcription factor NF-kappaB and proinflammatory pathway by measuring nuclear translocation of NF-kappaB and IL-6 secretion in vitro. Immunohistochemical and Western blot analysis and ELISA indicated that both nuclear p65 and secreted IL-6 were significantly (p<0.05) induced by UVB (20, 30 mJ/cm2) and UVA irradiation (10, 20 J/cm2). NF-kappaB nuclear translocation and IL-6 secretion induced by UVB and UVA were dramatically inhibited by treatment of EGCG. FACS analysis showed that EGCG also inhibited UVB-induced apoptosis. EGCG recovered UV-induced loss of anti-apoptotic component, bcl-2, and inhibited UV-induced apoptotic component, Fas ligand, expression. Collectively, we conclude that EGCG inhibits UVB- and UVA-induced proinflammatory pathway and inhibits apoptosis in cultured human keratinocytes in vitro. Our data suggest that EGCG be added to cosmetic or skin-care products for prevention from UV-induced skin photoaging if this activity can be further confirmed and no cytotoxicity is reported in human skin in vivo.
Asunto(s)
Apoptosis/efectos de los fármacos , Catequina/análogos & derivados , Interleucina-6/metabolismo , Queratinocitos/efectos de los fármacos , FN-kappa B/metabolismo , Protectores contra Radiación/farmacología , Factor de Transcripción ReIA/metabolismo , Rayos Ultravioleta , Catequina/farmacología , Regulación hacia Abajo , Proteína Ligando Fas , Humanos , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , Glicoproteínas de Membrana/metabolismo , Transporte de Proteínas/efectos de los fármacos , Transporte de Proteínas/efectos de la radiación , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Factores de Necrosis Tumoral/metabolismoRESUMEN
BACKGROUND: It is known that ultraviolet irradiation can affect cellular function through a number of signaling pathways. (-)-epigallocatechin-3-gallate (EGCG) is the major effective component in green tea and can offer protection from ultraviolet-induced damage. In this study, we investigated the protective mechanism of EGCG on human dermal fibroblasts damaged by ultraviolet A (UVA) in vitro. METHODS: Transcription factor Jun protein levels were measured by Western blot. Matrix metalloproteinase 1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA were studied by reverse transcription-polymerase chain reaction (RT-PCR) analysis in conjunction with computer-assisted image analysis. MMP-1 and TIMP-1 proteins were quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: EGCG decreased transcription activity of Jun protein after induction by UVA. Both the mRNA and protein levels of MMP-1 were increased by UVA irradiation, while no significant changes were observed in TIMP-1 levels. The ratio of MMP-1 to TIMP-1 showed statistically significant differences compared with the control. EGCG decreased the ratio of MMP-1 to TIMP-1 by inhibiting UVA-induced MMP-1 expression (P < 0.05). CONCLUSION: EGCG can protect human fibroblasts against UVA damage by downregulating the transcription activity of Jun protein and the expression of MMP-1. The ratio of MMP-1 to TIMP-1, rather than the levels of MMP-1 or TIMP-1 alone, may play a significant role in human skin photodamage.