RESUMEN
Thymic stromal lymphopoetin (TSLP) influences numerous immune functions, including those in the colonic mucosa. Here we report that TSLP-deficient (Tslp(-/-)) mice did not exhibit increased inflammation during dextran sodium sulfate (DSS)-induced colitis but failed to recover from disease, resulting in death. Increased localized neutrophil elastase (NE) activity during overt inflammation was observed in Tslp(-/-) mice and was paralleled by reduced expression of an endogenous inhibitor, secretory leukocyte peptidase inhibitor (SLPI). Pharmacological inhibition of NE or treatment with rSLPI reduced DSS-induced mortality in Tslp(-/-) mice. Signaling through TSLPR on nonhematopoietic cells was sufficient for recovery from DSS-induced colitis. Expression of the receptor occurred on intestinal epithelial cells (IEC), with stimulation inducing SLPI expression. Therefore, TSLP is critical in mediating mucosal healing after insult and functions in a nonredundant capacity that is independent of restraining T helper 1 (Th1) and Th17 cell cytokine production.
Asunto(s)
Colitis/inmunología , Inmunoglobulinas/metabolismo , Mucosa Intestinal/metabolismo , Elastasa de Leucocito/metabolismo , Receptores de Citocinas/metabolismo , Inhibidor Secretorio de Peptidasas Leucocitarias/metabolismo , Animales , Células Cultivadas , Colitis/inducido químicamente , Colitis/genética , Colitis/metabolismo , Colon/efectos de los fármacos , Colon/patología , Sulfato de Dextran/administración & dosificación , Regulación hacia Abajo , Activación Enzimática/efectos de los fármacos , Activación Enzimática/genética , Inmunidad Mucosa , Inflamación , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Elastasa de Leucocito/genética , Elastasa de Leucocito/inmunología , Ratones , Ratones Noqueados , Proteínas Recombinantes/genética , Inhibidor Secretorio de Peptidasas Leucocitarias/administración & dosificación , Inhibidor Secretorio de Peptidasas Leucocitarias/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
CD83 is the major surface marker identifying mature dendritic cells (DCs). In this study, we report the generation of reporter mice expressing EGFP under the control of the CD83 promoter. We have used these mice to characterize CD83 expression by various immune system cell types both in vivo and ex vivo and under steady-state conditions and in response to stimulation with a Toll-like receptor (TLR) ligand. With those mice we could prove in vivo that the CD83 promoter is highly active in all DCs and B cells in lymphoid organs. Interestingly, this promoter activity in B cells mainly depended on the stage of development, is up-regulated in the late pre-B cell stage, and was maintained on a high level in all peripheral B cells. We also confirmed that CD83 in those cells is mainly intracellular but is up-regulated after TLR stimulation. Otherwise, CD83 promoter activity in T cells seemed to depend on stimulation and could be found mainly in CD4(+)CD25(+) and CD8(+)CD25(+) T cells and in CD4(+) and CD8(+) memory cells. In addition, we identified the murine homologues of the human CD83 splice variants. In contrast to those in human, those extremely rare short transcripts were never found without the expression of the highly dominant full-length form. So, the murine CD83 surface expression is mainly regulated posttranslationally in vivo. Our CD83 reporter mice represent a useful mouse model for monitoring the activation status and migration of DCs and lymphocytes under various conditions, and our results provide much needed clarification of the true nature of CD83 promoter activity.