British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC, Canada.
J Leukoc Biol. 2010 Nov;88(5):925-35. doi: 10.1189/jlb.1209825. Epub 2010 Aug 18.
We demonstrate herein that SHIP negatively regulates the proliferation, differentiation, and survival of FL-DCs from BM precursors, as shown by a more rapid appearance and higher numbers of CD11c(+) DCs from SHIP-/- cultures as well as increased survival of mature FL-DCs in the absence of Flt3L. This increased survival, which is lost with low levels of the PI3K inhibitor, LY, correlates with an enhanced constitutive activation of the Akt pathway. Interestingly, however, these SHIP-/- FL-DCs display a less-mature phenotype after TLR ligand stimulation, as far as MHCII, CD40, and CD86 are concerned. Unexpectedly, SHIP-/- FL-DCs activated with TLR ligands, which use MyD88-independent pathways, are markedly impaired in their ability to stimulate Ag-specific T cell proliferation, and SHIP-/- FL-DCs activated by TLRs, which exclusively use the MyD88-dependent pathway, are as capable as WT FL-DCs. There is also a more pronounced T(H)1 skewing by the SHIP-/- FL-DCs than by WT FL-DCs, which is consistent with our finding that SHIP-/- FL-DCs secrete higher levels of IL-12 and TNF-α in response to LPS or dsRNA than their WT counterparts. These results suggest that SHIP negatively regulates FL-DC generation but positively regulates the maturation and function of FL-DCs induced by TLRs, which operate via MyD88-independent pathways.
我们在此证明，SHIP 负调节 BM 前体来源的 FL-DC 的增殖、分化和存活，这表现在 SHIP-/- 培养物中 CD11c(+) DC 更早出现且数量更多，以及在没有 Flt3L 的情况下成熟 FL-DC 的存活率增加。这种增加的存活率在 PI3K 抑制剂 LY 存在时会丢失，与 Akt 途径的组成性激活增强相关。然而，有趣的是，这些 SHIP-/- FL-DC 在 TLR 配体刺激后表现出较少成熟的表型，就 MHCII、CD40 和 CD86 而言。出乎意料的是，使用 MyD88 非依赖性途径的 TLR 配体激活的 SHIP-/- FL-DC 刺激 Ag 特异性 T 细胞增殖的能力显著受损，而仅使用 MyD88 依赖性途径的 TLR 激活的 SHIP-/- FL-DC 与 WT FL-DC 一样有能力。SHIP-/- FL-DC 比 WT FL-DC 更明显地偏向于 T(H)1，这与我们的发现一致，即 SHIP-/- FL-DC 在响应 LPS 或 dsRNA 时分泌更高水平的 IL-12 和 TNF-α。这些结果表明，SHIP 负调节 FL-DC 的产生，但正调节通过 MyD88 非依赖性途径起作用的 TLR 诱导的 FL-DC 的成熟和功能。
