RESUMEN
Patients suffering from ulcerative colitis (UC) exhibit chronic colonic inflammation caused by a dysregulated mucosal immune response and epithelial barrier disruption. Th2 cytokines, including IL-13, have been implicated in the pathogenesis of UC. IL-13 induces phosphorylation of STAT6, and we previously demonstrated increased epithelial p-STAT6 in children with UC. In this study, we investigated the role of STAT6 in oxazolone colitis, a murine model of UC, by inducing colitis in STAT6-deficient (STAT6(-/-)) and wild type (WT) mice. We observed increased epithelial cell, T cell, macrophage, and NKT cell STAT6 phosphorylation, as well as increased p-STAT6(+) IL-13-producing NKT cells, in colitic WT mice. Colitis was attenuated in STAT6(-/-) mice, with improvements in weight, colon length, and histopathology. There was decreased induction of the pore-forming tight junction protein claudin-2 in STAT6(-/-) mice. Similarly, short hairpin RNA STAT6 knockdown reduced claudin-2 induction and transepithelial resistance decrease in IL-13-treated human T84 cells. Tissue expression of IL-13, IFN-γ, IL-17, and IL-10 mRNA was similarly induced in WT and STAT6(-/-) colitic mice; however, we observed increased mRNA expression for the Th2-inducing cytokines IL-33 and thymic stromal lymphopoietin in WT mice with colitis, which was abrogated in STAT6(-/-) mice. Mesenteric lymph node cells from STAT6(-/-) mice with colitis exhibited reduced secretion of IL-4, IL-5, IL-13, and IFN-γ. IL-33 augmented mesenteric lymph node cell secretion of IL-5, IL-13, IL-6, and IFN-γ. These data implicate STAT6 in the pathogenesis of colitis in vivo with important roles in altering epithelial barrier function and regulating Th2-inducing cytokine production.
Asunto(s)
Claudina-2/antagonistas & inhibidores , Colitis Ulcerosa/inmunología , Citocinas/antagonistas & inhibidores , Regulación hacia Abajo/inmunología , Oxazolona/administración & dosificación , Factor de Transcripción STAT6/deficiencia , Índice de Severidad de la Enfermedad , Células Th2/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/efectos adversos , Adyuvantes Inmunológicos/antagonistas & inhibidores , Animales , Línea Celular , Claudina-2/biosíntesis , Claudina-2/genética , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/prevención & control , Citocinas/biosíntesis , Citocinas/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo/genética , Regulación de la Expresión Génica/inmunología , Haptenos/administración & dosificación , Haptenos/efectos adversos , Humanos , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Noqueados , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Células T Asesinas Naturales/patología , Oxazolona/efectos adversos , Oxazolona/antagonistas & inhibidores , Factor de Transcripción STAT6/genética , Células Th2/metabolismo , Células Th2/patologíaRESUMEN
Glycyrrhizin (18beta-glycyrrhetinic acid-3-O-beta-D-glucuronopyranosyl-(1 --> 2)-beta-D-glucuronide, GL) was transformed to 18beta-glycyrrhetinic acid-3-O-beta-D-glucuronide (GAMG) by Streptococcus LJ-22. The antiallergic activities of GL and GAMG was measured using a RBL cell assay system and contact hypersensitivity model mice. GAMG exhibited anti-allergic activity with IC50 values of 0.28 mM. GAMG, which is sweeter than GL, and 18beta-glycyrrhetinic acid, which is a GAMG metabolite by human intestinal bacteria, also inhibited the passive cutaneous anaphylaxis and skin contact inflammation. In conclusion, GAMG may be useful as a new sweet food additive and an anti-allergic agent.
Asunto(s)
Antialérgicos/farmacología , Glucurónidos/farmacología , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacología , Administración Oral , Animales , Antialérgicos/química , Antialérgicos/metabolismo , Línea Celular , Dermatitis por Contacto/prevención & control , Dexametasona/farmacología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Ácido Glicirretínico/metabolismo , Ácido Glicirrínico/química , Ácido Glicirrínico/metabolismo , Ácido Glicirrínico/farmacología , Humanos , Inyecciones Intraperitoneales , Intestinos/microbiología , Masculino , Ratones , Ratones Endogámicos ICR , Nitritos/antagonistas & inhibidores , Nitritos/metabolismo , Oxazolona/efectos adversos , Oxazolona/antagonistas & inhibidores , Oxazolona/inmunología , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Anafilaxis Cutánea Pasiva/fisiología , Streptococcus/efectos de los fármacos , Streptococcus/metabolismo , beta-N-Acetilhexosaminidasas/antagonistas & inhibidores , beta-N-Acetilhexosaminidasas/metabolismoRESUMEN
Epicutaneous application of haptens to UV-exposed skin induces hapten-specific tolerance. This is mediated via regulatory T cells (Tr), as i.v. injection of T cells from UV-tolerized mice into naive animals renders the recipients unresponsive to the respective hapten. However, when UV-induced Tr are injected i.v. into sensitized mice, contact hypersensitivity (CHS) is not suppressed, suggesting that Tr inhibit the induction, but not the elicitation, of CHS and are inferior to T effector cells. As sensitization takes place in the lymph nodes, but elicitation occurs in the area of challenge, we postulated that Tr injected i.v. locate to the lymph nodes and not to the periphery and therefore only suppress the induction, not the elicitation, of CHS. Indeed, i.v. injection of Tr into sensitized mice did not inhibit CHS, although injection of Tr into the ears of sensitized mice suppressed the challenge. Inhibition was hapten specific, as injection of dinitrofluorobenzene (DNFB)-specific Tr into the ears of oxazolone (OXA)-sensitized mice did not affect challenge with OXA. However, when ears of OXA-sensitized mice were injected with DNFB-specific Tr and painted with DNFB before OXA challenge, CHS was suppressed. Inhibition correlated with the local expression of IL-10. Depletion studies and FACS analysis revealed that Tr express the lymph node-homing receptor L-selectin, but not the ligands for the skin-homing receptors E- and P-selectin, suggesting that UV-induced Tr, although able to inhibit T effector cells, do not suppress the elicitation of CHS upon i.v. injection, because they obviously do not migrate into the skin.
Asunto(s)
Dermatitis por Contacto/inmunología , Dermatitis por Contacto/prevención & control , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de la radiación , Rayos Ultravioleta , Traslado Adoptivo , Animales , Dinitrofluorobenceno/administración & dosificación , Oído Externo , Haptenos/administración & dosificación , Haptenos/inmunología , Inmunización , Inmunofenotipificación , Inyecciones Intradérmicas , Inyecciones Intravenosas , Selectina L/biosíntesis , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Ratones , Ratones Endogámicos C3H , Oxazolona/antagonistas & inhibidores , Oxazolona/inmunología , Receptores de Interleucina-2/biosíntesis , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/efectos de la radiación , Subgrupos de Linfocitos T/trasplante , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/trasplanteRESUMEN
New anti-irritant treatments are required to prevent irritation and sensitization reactions to consumer medicines and dermatological drugs. We report here that phenoxyacetic acid methyl ester (PAME) is an effective agent to prevent and treat irritant and allergic contact dermatitis. Balb/c mice skin-treated with 1% PAME do not lose weight relative to vehicle-treated mice, nor is it irritating to mouse skin. Topical PAME prevents skin irritation to a wide variety of irritants including: arachidonic acid, capsaicin, sodium lauryl sulfate (SLS), disodium laureth sulfosuccinate and tetradecanoylphorbol-13-acetate. Histological studies showed that 1% PAME greatly diminished dermal neutrophilic infiltration and dermal capillary vessel dilation, and prevented epidermal hyperproliferation and hyperkeratosis that accompanies detergent (SLS)-induced skin irritation. Topical PAME inhibited ear swelling following ear challenge during the elicitation phase of contact hypersensitivity in mice sensitized with 1-chloro-2, 4-dinitrochlorobenzene (DNCB), oxazolone and the hair coloring dye rho-phenylenediamine (PPD). Finally, topical administration of 1% PAME prior to PPD or DNCB sensitization prevented the induction phase of contact hypersensitivity. These results indicate that PAME represents a potential new category of potent topical anti-inflammatory agents.
Asunto(s)
Dermatitis Alérgica por Contacto/tratamiento farmacológico , Irritantes/antagonistas & inhibidores , Fenilacetatos/uso terapéutico , Administración Tópica , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/uso terapéutico , Dermatitis Alérgica por Contacto/patología , Dinitroclorobenceno/antagonistas & inhibidores , Dinitroclorobenceno/toxicidad , Diuresis/efectos de los fármacos , Oído Externo/patología , Femenino , Irritantes/toxicidad , Ratones , Ratones Endogámicos BALB C , Oxazolona/análogos & derivados , Oxazolona/antagonistas & inhibidores , Oxazolona/toxicidad , Fenilacetatos/administración & dosificación , Fenilendiaminas/antagonistas & inhibidores , Fenilendiaminas/toxicidad , Tensoactivos/toxicidadRESUMEN
Ciclosporin is clinically effective in a variety of inflammatory skin diseases. We have therefore studied the effects of the drug on cutaneous inflammation in mice. Ciclosporin inhibited the inflammatory response to 12-O-tetradecanoylphorbol-13-acetate (TPA) and to the contact sensitising agent oxazolone when applied topically to mouse skin. The drug had no effect on arachidonic acid-induced inflammation. The protein synthesis inhibitor cycloheximide showed a similar profile of activity. Ciclosporin, like actinomycin D but unlike cycloheximide, was only effective in inhibiting the inflammatory response to TPA if given 0.5 h before, but not 2 h, after TPA. These results suggest that the anti-inflammatory activity of ciclosporin in the skin is due to an effect on the production of proinflammatory proteins.
Asunto(s)
Antiinflamatorios no Esteroideos , Ciclosporinas/farmacología , Dermatitis/tratamiento farmacológico , Inhibidores de la Síntesis de la Proteína/farmacología , Animales , Ácido Araquidónico , Ácidos Araquidónicos/antagonistas & inhibidores , Cicloheximida/farmacología , Dactinomicina/farmacología , Dermatitis/patología , Femenino , Hipersensibilidad Tardía/tratamiento farmacológico , Ratones , Ratones Endogámicos , Neutrófilos/enzimología , Neutrófilos/metabolismo , Oxazolona/antagonistas & inhibidores , Peroxidasa/metabolismo , Piel/patología , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
11 beta-Hydroxy-16 alpha, 17 alpha, 21-trimethyl-pregna-1,4-diene-3,20-dione(ORG 6216) is a novel type of anti-inflammatory steroid which displays a dissociation of local from systemic effects in a range of animal models. Moreover, ORG 6216 is exceptional in that it has not shown any significant atrophogenic activity in the skin when administered either topically or intracutaneously in animal models.
Asunto(s)
Antiinflamatorios/farmacología , Administración Tópica , Animales , Antiinflamatorios/administración & dosificación , Colágeno/biosíntesis , Edema/tratamiento farmacológico , Eritema/tratamiento farmacológico , Glucocorticoides , Inyecciones Subcutáneas , Glucógeno Hepático/biosíntesis , Masculino , Ratones , Oxazolona/antagonistas & inhibidores , PregnadienosRESUMEN
The effect of levamisole upon cell-mediated immunity was investigated using the oxazolone-induced contact sensitivity response in immunosuppressed and nonimmunosuppressed C57Bl male mice. Mice were sensitized to oxazolone on day 0, and where appropriate, methotrexate (1 mg/kg, p.o.) was administered on days 1 and 2. On day 3, levamisole (5--50 mg/kg, p.o., base) was administered. One hour later, the animals were challenged with oxazolone on the left hindpaw. Twenty-four hours after challenge, the resulting edema was read plethysmographically. Levamisole, in the absence of immunosuppression, had no significant effect upon the oxazolone response whereas, in the face of immunosuppression, restoration of oxazolone responsiveness was observed. These results were suggested to be due to (1) the ability of levamisole to stimulate opposing suppressor and effector components of the oxazolone response coupled with (2) an apparent alteration of suppressor influence by methotrexate allowing levamisole to enhance an unencumbered effector cell population.