RESUMEN
Atopic dermatitis (AD) is a common chronic skin inflammatory disease. Long-term use of topical corticosteroids in skin inflammation poses risks of systemic and local side effects. The NF-kappaB transcription factor family plays a central role in the progression and maintenance of AD. This study explores the possibility of using topical NF-kappaB Decoy as a novel therapeutic alternative for targeting Th1/Th2-driven skin inflammation in experimental AD. A high-affinity, topical NF-kappaB Decoy developed for human efficacy demonstrates: (i) efficient NF-kappaB Decoy penetration in pig skin, (ii) NF-kappaB Decoy nuclear localization in keratinocytes and key immune cells, and (iii) potent "steroid-like" efficacy in a chronic dust-mite antigen skin inflammation treatment model. NF-kappaB Decoy exerts its anti-inflammatory action through the effective inhibition of essential regulators of inflammation and by induction of apoptosis of key immune cells. Unlike betamethasone valerate (BMV), long-term NF-kappaB Decoy treatment does not induce skin atrophy. Moreover, topical NF-kappaB Decoy, in contrast to BMV, restores compromised stratum corneum integrity and barrier function. Steroid withdrawal causes rapid rebound of inflammation, while the NF-kappaB Decoy therapeutic benefit was maintained for weeks. Thus, topical NF-kappaB Decoy provides a novel mechanism of reducing chronic skin inflammation with improved skin homeostasis and minimal side effects.
Asunto(s)
Dermatitis Atópica/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Oligodesoxirribonucleótidos/administración & dosificación , Piel/efectos de los fármacos , Administración Tópica , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Atrofia , División Celular/efectos de los fármacos , División Celular/inmunología , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Oído Externo , Edema/tratamiento farmacológico , Edema/inmunología , Masculino , Ratones , Ratones Endogámicos , Pomadas , Permeabilidad/efectos de los fármacos , Piel/inmunología , Piel/patologíaRESUMEN
RDP58 is the first lead compound in a series of immunomodulating decapeptides discovered through activity-based screening and computer-aided, rational design. RDP58 disrupts cellular responses signaled through the Toll-like and tumor necrosis factor (TNF) receptor families and occludes important signal transduction pathways involved in inflammation, inhibiting the production of tumor necrosis factor alpha (TNFalpha), interferon-gamma, interleukin (IL)-2, IL-6, and IL-12. These pro-inflammatory cytokines are thought to be involved in the pathogenesis of several inflammatory and autoimmune diseases, including atopic dermatitis and psoriasis. The goal of this study was to determine the ability of RDP58 to inhibit skin inflammation following exposure to the well-characterized protein kinase C activator and tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical application of RDP58 to the epidermis following TPA treatment resulted in the amelioration of the phorbol ester-induced irritant contact dermatitis. Substantial reductions were observed in skin thickness and tissue weight, neutrophil-mediated myeloperoxidase activity, inflammatory cytokine production, and various histopathological indicators. We also found RDP58 to be effective in reducing the compounding inflammatory damage brought on by chronic TPA exposure, and that it is capable of targeting inflammatory mediators specifically in the keratinocyte. These results demonstrate that topically applied RDP58 is an effective anti-inflammatory treatment in the phorbol ester-induced dermatitis model, and suggest that it may have therapeutic potential in a variety of immune-related cutaneous diseases.
Asunto(s)
Dermatitis Irritante/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Péptidos/uso terapéutico , Administración Tópica , Animales , Citocinas/metabolismo , Dermatitis Irritante/patología , Factores Inmunológicos/administración & dosificación , Mediadores de Inflamación/antagonistas & inhibidores , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Ratones , Activación Neutrófila/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Péptidos/administración & dosificación , Peroxidasa/metabolismo , Acetato de Tetradecanoilforbol/toxicidadRESUMEN
BACKGROUND: Nuclear factor-kappaB (NF-kappaB) is a key transcriptional regulator of inflammatory bowel disease (IBD). AIM: To investigate the therapeutic potential of a locally administered "non-viral" nuclear factor-kappaB decoy (NFkappaBD) in multiple experimental models of IBD. METHODS: A fully phosphorothioated decoy oligonucleotide with improved stability that specifically binds NF-kappaB and blocks inflammatory mediators regulated by this transcription factor without the help of viral envelope-assisted delivery was developed. The therapeutic effects of NFkappaBD were studied in the trinitrobenzene sulphonic acid, oxazolone and dextran sodium sulphate induced colitis models. RESULTS: Intracolonic administration of NFkappaBD results in the delivery of NFkappaBD to inflammatory cells and a reduction of NF-kappaB heterodimers. In the T helper cell 1-driven trinitrobenzene sulphonic acid-induced colitis model, mice receiving NFkappaBD treatment exhibit a dose-dependent reduction in disease severity and a more rapid recovery to normal body weight, similar to a clinically relevant dose of budesonide. Clinical efficacy was corroborated by considerable reductions in colitis pathology and tissue levels of several pro-inflammatory markers, including tumour necrosis factor alpha, interleukin 6, interleukin 1beta and monocyte chemotactic protein 1. NFkappaBD also mitigates disease activity in the T helper cell 2-like oxazolone colitis and epithelial injury-related acute dextran sodium sulphate colitis models. Interestingly, restoration of tissue homeostasis is observed in NFkappaBD-treated animals with the rapid re-emergence of functional goblet cells and a return to normal patterns of cell proliferation in the mucosal epithelium and smooth muscle cell layers. CONCLUSIONS: These data support the potential use of "naked" NFkappaBD as a cross-functional therapeutic in IBD, and show for the first time that it can facilitate the restoration of colon homeostasis and function.