RESUMEN
The basic helix-loop-helix transcriptional repressor twist1, as an antagonist of nuclear factor kappaB (NF-kappaB)-dependent cytokine expression, is involved in the regulation of inflammation-induced immunopathology. We show that twist1 is expressed by activated T helper (Th) 1 effector memory (EM) cells. Induction of twist1 in Th cells depended on NF-kappaB, nuclear factor of activated T cells (NFAT), and interleukin (IL)-12 signaling via signal transducer and activator of transcription (STAT) 4. Expression of twist1 was transient after T cell receptor engagement, and increased upon repeated stimulation of Th1 cells. Imprinting for enhanced twist1 expression was characteristic of repeatedly restimulated EM Th cells, and thus of the pathogenic memory Th cells characteristic of chronic inflammation. Th lymphocytes from the inflamed joint or gut tissue of patients with rheumatic diseases, Crohn's disease or ulcerative colitis expressed high levels of twist1. Expression of twist1 in Th1 lymphocytes limited the expression of the cytokines interferon-gamma, IL-2, and tumor necrosis factor-alpha, and ameliorated Th1-mediated immunopathology in delayed-type hypersensitivity and antigen-induced arthritis.
Asunto(s)
Inflamación/etiología , Proteínas Nucleares/metabolismo , Células TH1/inmunología , Proteína 1 Relacionada con Twist/metabolismo , Animales , Artritis Experimental/genética , Artritis Experimental/inmunología , Artritis Experimental/metabolismo , Artritis Experimental/patología , Secuencia de Bases , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/metabolismo , Cartilla de ADN/genética , Expresión Génica , Homeostasis , Humanos , Memoria Inmunológica , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Interleucina-12/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos MRL lpr , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , FN-kappa B/metabolismo , Factores de Transcripción NFATC/metabolismo , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Transducción de Señal , Células TH1/metabolismo , Proteína 1 Relacionada con Twist/deficiencia , Proteína 1 Relacionada con Twist/genéticaRESUMEN
In epidermal Langerhans cells (LCs), the expression pattern and the functions of TLRs have been poorly characterized. By using mAb, we show that LCs from human skin express TLR1, -2, -5, -6, and -9, the cognate receptors for detection of specific bacteria-derived molecules. As compared with other TLR agonists, LCs acquired a more matured phenotype when activated by specific bacterial or synthetic TLR2 agonists. In addition, monocyte-derived Langerin(+)/CD1c(+)LCs (CD1c(+)MoLCs) secreted higher amounts of IL-6 and TNF-alpha by stimulation via TLR2 than by stimulation via TLR3, -4, -5, -8, and -9. In contrast to MoLCs, dendritic cells, generated from the same donor monocytes, were activated by agonists of TLRs other than TLR2 as well. Lipopeptides triggering TLR2 induced IL-1R-associated kinase-1 phosphorylation and migration toward the chemokines CCL19 and CCL21 in epidermal LCs and CD1c(+)MoLCs. Up-regulation of CD86, CD83, and CCR7, TNF-alpha and IL-6, and NF-kappaB activation and proliferation of CD4(+)T cells could be inhibited TLR2-specific blockage using antibodies prior to TLR2 activation. Application of anti-TLR1, anti-TLR6, and anti-TLR2 indicated an exclusive role of TLR2 in IL-6 induction in human LCs. Collectively, our results show that TLR2 expressed by LCs mediates inflammatory responses to lipopeptides, which implicates a central role in sensing pathogens in human skin.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Células de Langerhans/inmunología , Activación de Linfocitos , Receptor Toll-Like 2/fisiología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/fisiología , Movimiento Celular , Células Epidérmicas , Citometría de Flujo , Humanos , Inflamación/inducido químicamente , Inflamación/prevención & control , Interleucina-6/metabolismo , Células de Langerhans/citología , Células de Langerhans/fisiología , Lipoproteínas/farmacología , FN-kappa B/análisis , Receptor Toll-Like 2/agonistas , Receptor Toll-Like 2/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
In Th1 and Th2 memory lymphocytes, the genes for the cytokines interleukin (IL)-4 and interferon-gamma (IFN-gamma) are imprinted for expression upon restimulation. This cytokine memory is based on expression of the transcription factors T-bet for IFN-gamma, and GATA-3 for IL-4, and epigenetic modification of the cytokine genes. In Th2 cells, expression of the cytokine IL-10 is also induced by GATA-3. Here, we show that this induction is initially not accompanied by epigenetic modification of the IL-10 gene. Only after repeated restimulation of a memory Th2 cell in the presence of IL-4, extensive histone acetylation of the IL-10 gene is detectable. This epigenetic imprinting correlates with the development of a memory for IL-10 in repeatedly restimulated Th2 cells. In Th1 cells, IL-10 expression is induced by IL-12, but the IL-10 gene lacks detectable histone acetylation. Accordingly, IL-10 expression in restimulated memory Th1 cells remains conditional on the presence of IL-12. This finding defines a potential anti-inflammatory role for IL-12 in Th1 recall responses. While in primary Th1 responses IL-12 is required to induce expression of the pro-inflammatory cytokine IFN-gamma, in secondary Th1 responses IFN-gamma re-expression is independent of IL-12, which still is able to induce expression of the anti-inflammatory cytokine IL-10.