Lucas Mark, Stuart Lynda M, Savill John, Lacy-Hulbert Adam
University of Edinburgh/MRC Center for Inflammation Research, University of Edinburgh, College of Medicine and Veterinary Medicine, Teviot Place, Edinburgh EH8 9AG, Scotland, UK.
J Immunol. 2003 Sep 1;171(5):2610-5. doi: 10.4049/jimmunol.171.5.2610.
Macrophage interactions with apoptotic cells can suppress inflammatory responses, but cell death by apoptosis may also trigger inflammation. We now report that murine macrophages exposed to the combination of apoptotic cells and archetypal ligands for Toll-like receptors (TLRs) 2, 4, and 9 mount cytokine responses that differ importantly from those elicited by either class of stimulus alone. TLR ligands induced early and sustained secretion of TNF-alpha, macrophage-inflammatory protein (MIP) 1alpha and MIP-2 with later secretion of IL-10, IL-12, and TGF-beta1; apoptotic cells alone stimulated late TGF-beta1 secretion only. The combination of apoptotic cells and TLR ligands enhanced early secretion of TNF-alpha, MIP-1alpha, and MIP-2 and increased late TGF-beta1 secretion, while suppressing late TNF-alpha, IL-10, and Il-12 by mechanisms which could nevertheless be overridden by IFN-gamma. We propose that this combinatorial macrophage cytokine response to apoptotic cells and TLR ligands may contribute to recruitment and activation of innate immune defense when cell death occurs at infected inflamed sites while promoting later resolution with diminished engagement of adaptive immunity.
巨噬细胞与凋亡细胞的相互作用可抑制炎症反应，但凋亡引起的细胞死亡也可能引发炎症。我们现在报告，暴露于凋亡细胞与Toll样受体（TLR）2、4和9的典型配体组合的小鼠巨噬细胞产生的细胞因子反应，与单独由任何一类刺激引发的反应有重要差异。TLR配体诱导肿瘤坏死因子-α（TNF-α）、巨噬细胞炎性蛋白（MIP）1α和MIP-2的早期持续分泌，随后分泌白细胞介素-10（IL-10）、IL-12和转化生长因子-β1（TGF-β1）；单独的凋亡细胞仅刺激晚期TGF-β1分泌。凋亡细胞与TLR配体的组合增强了TNF-α、MIP-1α和MIP-2的早期分泌，并增加了晚期TGF-β1分泌，同时通过某些机制抑制晚期TNF-α、IL-10和IL-12的分泌，不过这些机制可被干扰素-γ（IFN-γ）克服。我们提出，这种巨噬细胞对凋亡细胞和TLR配体的组合性细胞因子反应，在感染的炎症部位发生细胞死亡时，可能有助于先天免疫防御的募集和激活，同时通过减少适应性免疫的参与促进后期炎症的消退。
