Pattern-recognition receptors,such as toll-like receptors(TLRs),detect a wide range of microbial products and initiate innate immune responses leading to the production of inflammatory mediators.In addition,TLR signal...Pattern-recognition receptors,such as toll-like receptors(TLRs),detect a wide range of microbial products and initiate innate immune responses leading to the production of inflammatory mediators.In addition,TLR signaling also activates expression of Notch target genes that play crucial roles in suppression of TLR-triggered inflammatory responses.However,whether TLR signaling pathways engaged by other classes of pattern-recognition receptors induce expression of Notch target genes remains unclear.Here we demonstrate that zymosan,a stimulus for TLR2 and dectin-1,strongly induces expression of multiple Notch target genes in both human and murine dendritic cells.Mechanistically,induction of Notch targets by zymosan is both TLR2-and Syk-dependent through activation of mitogen-activated protein kinases and the transcription factor c-Fos.Hence,our data reveals a novel mechanism that efficient induction of Notch target genes requires engagement of TLR and dectin-1/Syk signaling pathways.展开更多
A key and limiting step in the process of human monocyte-derived dendritic cells (mDCs) for clinical use is their in vitro maturation and in vivo migration. We previously observed that CD40 signal facilitated human mD...A key and limiting step in the process of human monocyte-derived dendritic cells (mDCs) for clinical use is their in vitro maturation and in vivo migration. We previously observed that CD40 signal facilitated human mDC growth and maturation. To further explore this process,mDCs generated with GM-CSF and IL-4 were co-cultured with apoptotic tumor cells for 24 hours,followed by incubating with anti-CD40 monoclonal antibody or TNF-α for 48 hours to generate mature DCs. The chemokine/chemokine receptor expression and functions of mature DCs upon various stimuli were determined. The expression of costimulatory molecules on apoptotic tumor cell-loaded mature DCs co-cultured with either anti-CD40 antibody (anti-CD40-DCs) or TNF-α (TNF-DCs) were up-regulated compared to immature DCs,consistent with the abilities of these cytokine to drive DC maturation in vitro. The mRNA levels of chemokines such as stromal cell-derived factor-1α (SDF-1α),EBV-induced molecule 1 ligand chemokine (ELC),and IFN inducible protein-10 (IP-10) in anti-CD40 activated DCs were increased and the dendritic cell-specific chemokine 1 (DC-CK1) was moderately up-regulated as compared with other mature DCs. The corresponding chemokine receptors CXCR4 and CCR7 of anti-CD40-DCs were significantly expressed. The CXCR3 expression on activated T cells stimulated by anti-CD40-DCs was also increased. Moreover,the anti-CD40-DCs had a stronger ability to stimulate T cell proliferation than any other DCs. The NF-κB activity was much higher in anti-CD40-DCs than that of TNF-DCs. These results offer further evidence of the importance of the CD40 signal in developing efficient human DC vaccines for cancer immune therapy.展开更多
基金supported by grants from the National Natural Science Foundation of China 31725010 and 31821003(XH),grant from the Shandong Provincial Natural Science Foundation,China ZR2017MC021(YS)funds from the Tsinghua-Peking Center for Life Sciences and Institute for Immunology at Tsinghua University(XH),funds from the Peak Discipline Construction Plan of Shandong Province and Shandong Agricultural University(YS),and grants from the NIH(BZ).
文摘Pattern-recognition receptors,such as toll-like receptors(TLRs),detect a wide range of microbial products and initiate innate immune responses leading to the production of inflammatory mediators.In addition,TLR signaling also activates expression of Notch target genes that play crucial roles in suppression of TLR-triggered inflammatory responses.However,whether TLR signaling pathways engaged by other classes of pattern-recognition receptors induce expression of Notch target genes remains unclear.Here we demonstrate that zymosan,a stimulus for TLR2 and dectin-1,strongly induces expression of multiple Notch target genes in both human and murine dendritic cells.Mechanistically,induction of Notch targets by zymosan is both TLR2-and Syk-dependent through activation of mitogen-activated protein kinases and the transcription factor c-Fos.Hence,our data reveals a novel mechanism that efficient induction of Notch target genes requires engagement of TLR and dectin-1/Syk signaling pathways.
基金the National Natural Science Foundation of China （No 30330540 and No 30572120） by Ministry of Science and Technology of China 973 Basic Science Project 2007CB512402 863 Basic Science Project 2006AA02A254.
文摘A key and limiting step in the process of human monocyte-derived dendritic cells (mDCs) for clinical use is their in vitro maturation and in vivo migration. We previously observed that CD40 signal facilitated human mDC growth and maturation. To further explore this process,mDCs generated with GM-CSF and IL-4 were co-cultured with apoptotic tumor cells for 24 hours,followed by incubating with anti-CD40 monoclonal antibody or TNF-α for 48 hours to generate mature DCs. The chemokine/chemokine receptor expression and functions of mature DCs upon various stimuli were determined. The expression of costimulatory molecules on apoptotic tumor cell-loaded mature DCs co-cultured with either anti-CD40 antibody (anti-CD40-DCs) or TNF-α (TNF-DCs) were up-regulated compared to immature DCs,consistent with the abilities of these cytokine to drive DC maturation in vitro. The mRNA levels of chemokines such as stromal cell-derived factor-1α (SDF-1α),EBV-induced molecule 1 ligand chemokine (ELC),and IFN inducible protein-10 (IP-10) in anti-CD40 activated DCs were increased and the dendritic cell-specific chemokine 1 (DC-CK1) was moderately up-regulated as compared with other mature DCs. The corresponding chemokine receptors CXCR4 and CCR7 of anti-CD40-DCs were significantly expressed. The CXCR3 expression on activated T cells stimulated by anti-CD40-DCs was also increased. Moreover,the anti-CD40-DCs had a stronger ability to stimulate T cell proliferation than any other DCs. The NF-κB activity was much higher in anti-CD40-DCs than that of TNF-DCs. These results offer further evidence of the importance of the CD40 signal in developing efficient human DC vaccines for cancer immune therapy.
基金Supported by grants of Medical Science and Technology Development Foundation, Jiangsu Province Department of Health (No. H201013)the Program for Postgraduate Research Innovation in University of Jiangsu Province (No. CX10B_054Z)the Project of Youth Foundation in Science and Education of Department of Public Health of Suzhou (2010, No. 4)
