ABSTRACT
BACKGROUND: Photodynamic therapy (PDT) using aminolevulinic acid (ALA) with blue light or red light is effective for treating actinic keratoses (AKs). However, immunosuppression follows red light PDT, raising the spectre of skin cancer promotion in treated skin. OBJECTIVE: To determine whether broad-area short incubation (BASI)-ALA-PDT using blue light immunosuppression immunosuppresses treated skin. METHODS: Patients were evaluated clinically and by standardized facial biopsies of non-AK skin before, 24 hours and 1 month after customary blue light BASI-ALA-PDT. All biopsies were stained for markers of epidermal atypia and Langerhans cells (LCs); and at 24 hours to detect oxidative DNA damage. RESULTS: Patients had an 81% reduction in AKs and slight improvement in clinical and histologic signs of photoaging after 1 month. The biopsied chronically photodamaged skin without clinically detectable AKs showed no effect of PDT on the LC number, distribution, or morphology; and no oxidative DNA damage, in contrast to the changes reported after customary red light PDT. CONCLUSION: Customary blue light BASI-ALA-PDT does not affect the LC number or produce oxidative DNA damage, the sequelae of red light PDT responsible for immunosuppression in treated skin.
Subject(s)
DNA Damage , Keratosis, Actinic/drug therapy , Langerhans Cells/radiation effects , Photochemotherapy/methods , Skin Aging/radiation effects , Aged , Aminolevulinic Acid/pharmacology , Cell Count , Color , Female , Humans , Immunosuppression Therapy , Keratinocytes/chemistry , Keratosis, Actinic/pathology , Ki-67 Antigen/analysis , Langerhans Cells/drug effects , Male , Middle Aged , Oxidative Stress , Photochemotherapy/adverse effects , Photosensitizing Agents/pharmacology , Skin Aging/drug effects , Skin Aging/pathology , Tumor Suppressor Protein p53/analysisSubject(s)
Alopecia/pathology , Adult , Alopecia/complications , Cicatrix/complications , Cicatrix/pathology , Face , Fibrosis/complications , Humans , Male , Middle AgedABSTRACT
Granular cell tumors are benign neurally derived neoplasms, involving cutaneous and subcutaneous tissues; and typically occur as solitary lesions. Multiple granular cell tumors occur in 10% of affected individuals, but are in children. Children with underlying somatic and genetic syndromes, including neurofibromatosis and Noonan syndrome, appear to be at higher risk of developing multiple granular cell tumors. Skin biopsy assists in diagnosis, since granular cell tumors have a similar appearance to other cutaneous nodules. Painful or rapidly growing granular cell tumors should be excised and asymptomatic non-growing granular cell tumors may be observed. Children with multiple granular cell tumors should have a complete physical examination to rule out an underlying genetic syndrome.
Subject(s)
Granular Cell Tumor/diagnosis , Neoplasms, Multiple Primary/diagnosis , Noonan Syndrome/diagnosis , Skin Neoplasms/diagnosis , Child , Female , Granular Cell Tumor/genetics , Granular Cell Tumor/pathology , Granular Cell Tumor/surgery , Humans , Neoplasms, Multiple Primary/genetics , Neoplasms, Multiple Primary/pathology , Neoplasms, Multiple Primary/surgery , Noonan Syndrome/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Skin Neoplasms/surgery , Treatment OutcomeABSTRACT
Mullerian-inhibiting substance (MIS), a transforming growth factor-beta family member, activates the nuclear factor-kappaB (NF-kappaB) pathway and induces the expression of B-cell translocation gene 2 (BTG2), IFN regulatory factor-1 (IRF-1), and the chemokine Gro-beta. Inhibiting NF-kappaB activation with a phosphorylation-deficient IkappaBalpha mutant abrogated MIS-mediated induction of all three genes. Expression of dominant-negative Smad1, in which serines at the COOH-terminal SSVS motif are converted to alanines, suppressed MIS-induced Smad1 phosphorylation and impaired MIS-stimulated Gro-beta promoter-driven reporter expression and Gro-beta mRNA. Suppressing Smad1 expression using small interfering RNA also mitigated MIS-induced Gro-beta mRNA, suggesting that regulation of Gro-beta expression by MIS was dependent on activation of NF-kappaB as well as Smad1. However, induction of IRF-1 and BTG2 mRNAs by MIS was independent of Smad1 activation. Characterization of kappaB-binding sequences within Gro-beta, BTG2, and IRF-1 promoters showed that MIS stimulated binding of p50 and p65 subunits to all three sites, whereas phosphorylated Smad1 (phospho-Smad1) protein was detectable only in the NF-kappaB complex bound to the kappaB site of the Gro-beta promoter. Consistent with these observations, chromatin immunoprecipitation assays showed recruitment of both phospho-Smad1 and p65 to the Gro-beta promoter in vivo, whereas p65, but not phospho-Smad1, was recruited to the BTG2 promoter. These results show a novel interaction between MIS-stimulated Smad1 and NF-kappaB signaling in which enhancement of NF-kappaB DNA binding and gene expression by phospho-Smad1 is dependent on the sequence of the kappaB consensus site within the promoter.
