Elevated interleukin-6 and G-CSF in human pancreatic cancer cell conditioned medium suppress dendritic cell differentiation and activation
Elevated interleukin-6 and G-CSF in human pancreatic cancer cell conditioned medium suppress dendritic cell differentiation and activation
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DOI：
10.1158/0008-5472.can-06-3963
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发表时间：
2007-06-01
期刊：
影响因子：
11.2
通讯作者：
Yao, Qizhi
中科院分区：
文献类型：
--
作者：
Bharadwaj, Uddalak;Li, Min;Yao, Qizhi
虽然胰腺癌患者的树突状细胞（DC）功能受损，但其潜在机制尚不清楚。本研究分析了胰腺癌细胞释放的可溶性因子抑制DC分化和活化。本研究主要使用高转移性人胰腺癌细胞系BxPC-3的条件培养基[BxPC-3条件培养基（BxCM）]。BxCM抑制CD 34（+）造血祖细胞和CD 14（+）单核细胞来源的未成熟DC和成熟DC（mDC）。BxCM处理的mDC对CD 4（+）和CD 8（+）T细胞的同种异体刺激是无效的，并导致产生较低水平的Th 1和Th 2细胞因子。在BxCM处理的mDC中，抗原特异性T细胞活化能力也降低。加入外源性白细胞介素-6（IL-6）和粒细胞集落刺激因子（G-CSF），这是目前在BxCM中的高金额，模仿BxCM对DC分化和成熟的抑制作用。IL-6可抑制DC的分化，G-CSF主要作用于DC的同种异体刺激抑制能力。此外，胰腺癌患者血清能够抑制从健康供体获得的CD 14（+）单核细胞的DC分化。从BxCM中去除IL-6或G-CSF可以逆转BxCM的DC抑制特性。BxCM、IL-6、G-CSF可不同程度地激活CD 14（+）单核细胞信号转导子和转录激活子3（STAT 3）。阻断BxCM诱导的STAT 3活化也逆转了BxCM对DC分化的抑制作用。因此，BxCM中的IL-6和G-CSF代表了负责抑制DC分化、成熟和抗原呈递的两个主要因素，并且这种DC功能的抑制可能是由于BxCM对STAT 3的异常激活。
Although dendritic cell (DC) function is impaired in pancreatic cancer patients, the underlying mechanisms are unknown. This study analyzed the soluble factors released by pancreatic cancer cells responsible for inhibiting DC differentiation and activation. Medium conditioned by a highly metastatic human pancreatic cancer cell line BxPC-3 [BxPC-3 conditioned medium (BxCM)] was mainly used for the study. Both CD34(+) hematopoictic progenitor cell-derived and CD14(+) monocyte-derived immature DCs and mature DCs (mDCs) were inhibited by BxCM. Allostimulation of CD4(+) and CD8(+) T cells by BxCM-treated mDCs was inefficient and resulted in production of lower levels of Th1 and Th2 cytokines. Antigen-specific T-cell activation capability was also reduced in BxCM-treated mDCs. Addition of exogenous interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF), which were present in high amounts in BxCM, mimicked the inhibitory effect of BxCM on DC differentiation and maturation. IL-6 was able to suppress DC differentiation and G-CSF mainly acted on the suppressing allostimulatory capacity of DCs. In addition, pancreatic cancer patient sera were able to inhibit DC differentiation of CD14(+) monocytes obtained from healthy donors. Depleting IL-6 or G-CSF from BxCM could reverse the DC-inhibitory properties of BxCM. Furthermore, BxCM, IL-6, or G-CSF led to the activation of signal transducer and activator of transcription 3 (STAT3) in CD14(+) monocytes to different degrees. Blocking BxCM-induced STAT3 activation also reversed the inhibitory effect of BxCM on DC differentiation. Therefore, IL-6 and G-CSF in BxCM represent two main factors responsible for suppression of DC differentiation, maturation, and antigen presentation, and this suppression of DC functions may be due to the aberrant activation of STAT3 by BxCM.