The KG Jebsen Center for Myeloma Research and Faculty of Medicine, Department of Cancer Research and Molecular Medicine Norwegian University of Science and Technology (NTNU) Trondheim Norway.
Centre of Molecular Inflammation Rearch (CEMIR) NTNU Trondheim Norway.
Immun Inflamm Dis. 2016 Jul 21;4(3):327-37. doi: 10.1002/iid3.117. eCollection 2016 Sep.
Mesenchymal stem cells, also called mesenchymal stromal cells, MSCs, have great potential in stem cell therapy partly due to their immunosuppressive properties. How these cells respond to chronic inflammatory stimuli is therefore of importance. Toll-like receptors (TLR)s are innate immune receptors that mediate inflammatory signals in response to infection, stress, and damage. Caspase-8 is involved in activation of NF-kB downstream of TLRs in immune cells. Here we investigated the role of caspase-8 in regulating TLR-induced cytokine production from human bone marrow-derived mesenchymal stromal cells (hBMSCs).
Cytokine expression in hBMCs in response to poly(I:C) and LPS was evaluated by PCR, multiplex cytokine assay, and ELISA. TLR3, TRIF, and caspase-8 were silenced using siRNA. Caspase-8 was also inhibited using a caspase-8 inhibitor, z-IEDT.
We found that TLR3 agonist poly(I:C) and TLR4 agonist LPS induced secretion of several pro-inflammatory cytokines in a TLR-dependent manner which required the TLR signaling adaptor molecule TRIF. Further, poly(I:C) reduced the expression of anti-inflammatory cytokines HGF and TGFβ whereas LPS reduced HGF expression only. Notably, caspase-8 was involved in the induction of IL- IL-1β, IL-6, CXCL10, and in the inhibition of HGF and TGFβ.
Caspase-8 appears to modulate hBMSCs into gaining a pro-inflammatory phenotype. Therefore, inhibiting caspase-8 in hBMSCs might promote an immunosuppressive phenotype which could be useful in clinical applications to treat inflammatory disorders.
间充质干细胞，也称为间充质基质细胞，MSCs，由于其免疫抑制特性，在干细胞治疗中有很大的潜力。因此，这些细胞对慢性炎症刺激的反应非常重要。Toll 样受体（TLR）是先天免疫受体，可介导对感染、应激和损伤的炎症信号。Caspase-8 参与 TLR 下游 NF-kB 的激活在免疫细胞中。在这里，我们研究了 caspase-8 在调节 TLR 诱导的人骨髓间充质基质细胞（hBMSCs）产生细胞因子中的作用。
通过 PCR、多重细胞因子测定和 ELISA 评估 hBMCs 对 poly(I:C)和 LPS 的细胞因子表达。使用 siRNA 沉默 TLR3、TRIF 和 caspase-8。还使用 caspase-8 抑制剂 z-IEDT 抑制 caspase-8。
我们发现 TLR3 激动剂 poly(I:C)和 TLR4 激动剂 LPS 以 TLR 依赖的方式诱导几种促炎细胞因子的分泌，这需要 TLR 信号转导衔接分子 TRIF。此外，poly(I:C)降低了抗炎细胞因子 HGF 和 TGFβ的表达，而 LPS 仅降低了 HGF 的表达。值得注意的是，caspase-8 参与了 IL-1β、IL-6、CXCL10 的诱导，并抑制了 HGF 和 TGFβ 的表达。
caspase-8 似乎调节 hBMSCs 获得促炎表型。因此，抑制 hBMSCs 中的 caspase-8 可能会促进免疫抑制表型，这在治疗炎症性疾病的临床应用中可能有用。
