RESUMEN
It has recently been reported that the CD40-CD40 ligand (CD40L) interaction is important in Th17 development. In addition, transforming growth factor-beta (TGF-ß) promotes tumorigenesis as an immunosuppressive cytokine and is crucial in the development of Th17 cells. This study investigated the role of CD40 in breast cancer cells and its role in immunosuppressive function and tumor progression. CD40 was highly expressed in the breast cancer cell line MDA-MB231, and its stimulation with CD40 antibodies caused the up-regulation of TGF-ß. Direct CD40-CD40L interaction between MDA-MB231 cells and activated T cells also increased TGF-ß production and induced the production of IL-17, which accelerated the proliferation of MDA-MB231 cells through the activation of STAT3. Taken together, the direct CD40-CD40L interaction of breast tumor cells and activated T cells increases TGF-ß production and the differentiation of Th17 cells, which promotes the proliferation of breast cancer cells.
Asunto(s)
Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Antígenos CD40/metabolismo , Ligando de CD40/metabolismo , Linfocitos T/inmunología , Células Th17/inmunología , Factor de Crecimiento Transformador beta/biosíntesis , Neoplasias de la Mama/genética , Antígenos CD40/antagonistas & inhibidores , Antígenos CD40/genética , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Técnicas de Cocultivo , Femenino , Humanos , Interleucina-17/metabolismo , Activación de Linfocitos , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , ARN Interferente Pequeño/genética , Factor de Transcripción STAT3/metabolismo , Células Th17/patología , Factor de Crecimiento Transformador beta/genética , Regulación hacia ArribaRESUMEN
BACKGROUND: CM1 (centrocyte/-blast marker 1) was defined by a mAb against concanavalin A (Con A) activated PBMC. It is expressed in germinal center of human tonsil and on the surface of activated PBMC as well as cancer cells. Recently, increased productions of pro-inflammatory mediators were detected from activated PBMC by CM1 ligation. METHODS: However, there is a limitation to explain the exact role of CM1 on inflammation and its related mechanisms, since the identity of CM1 is still not clarified. In our previous study, we have already confirmed that soluble form of CM1 was produced by Raji. Therefore, we performed Q-TOF analysis after immunoprecipitation of concentrated Raji culture supernatant using anti-CM1 mAbs. RESULTS: As a result, we found that CM1 is identical to enolase-1(ENO1), a glycolytic enzyme, and we confirmed that results by silencing ENO1 using siRNA. It was also confirmed through competition assay between anti-CM1 and anti-ENO1 mAbs. Finally, we investigated the possible role of CM1 in inflammatory response and cancer. The ligation of CM1 on Raji cells with anti-CM1 mAbs induces the extensive production of prostaglandin E(2)(PGE(2)). In addition, the increased activity of matrix metalloproteinase (MMP)-2/9 was shown in NCI-N87, stomach cancer cell line by CM1 stimulation. CONCLUSION: CM1 is identical to ENO1 and it might be an important role in the regulation of inflammatory responses.