Mun Hye-Seong, Aosai Fumie, Norose Kazumi, Piao Lian-Xun, Fang Hao, Akira Shizuo, Yano Akihiko
Department of Infection and Host Defense, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Infect Immun. 2005 Aug;73(8):4634-42. doi: 10.1128/IAI.73.8.4634-4642.2005.
Peritoneal macrophages (PMs) from toll-like receptor 4 (TLR4)-deficient and wild-type (WT) mice were responsive to recombinant Toxoplasma gondii-derived heat shock protein 70 (rTgHSP70) and natural TgHSP70 (nTgHSP70) in NO release, but those from TLR2-, myeloid differentiation factor 88 (MyD88)-, and interleukin-1R-associated kinase 4 (IRAK4)-deficient mice were not. Polymyxin B did not inhibit PM activation by TgHSP70 and nTgHSP70 from WT and TLR4-deficient mice, while it inhibited PM activation by lipopolysaccharide. Pretreatment of PMs from WT but not from TLR4-deficient mice with rTgHSP70 resulted in suppression of NO release on restimulation with rTgHSP70. Similarly, pretreatment of PMs from WT but not TLR4-deficient mice with nTgHSP70 resulted in suppression of NO release on restimulation with nTgHSP70. Polymyxin B did not inhibit rTgHSP70- and nTgHSP70-induced tolerance of PMs from TLR4-deficient mice. Furthermore, PMs from WT mice increased suppressor of cytokine-signaling-1 (SOCS-1) expression after restimulation with rTgHSP70, while those from TLR4-deficient mice did not. Phosphorylation of JNK and I-kappaBalpha occurred in rTgHSP70-induced tolerance of PMs from TLR4-deficient mice, but not in that from WT mice. These data indicated that TgHSP70 signaling mechanisms were mediated by TLR2, MyD88, and IRAK4, but not by TLR4. On the other hand, signaling of TgHSP70-induced tolerance was mediated by TLR4, and the expression of SOCS-1 suppressed the TLR2 signaling pathway.
来自 toll 样受体 4（TLR4）缺陷型和野生型（WT）小鼠的腹腔巨噬细胞（PMs）对重组弓形虫来源的热休克蛋白 70（rTgHSP70）和天然 TgHSP70（nTgHSP70）的 NO 释放有反应，但来自 TLR2、髓样分化因子 88（MyD88）和白细胞介素-1R 相关激酶 4（IRAK4）缺陷型小鼠的 PMs 则无反应。多粘菌素 B 不抑制 WT 和 TLR4 缺陷型小鼠的 TgHSP70 和 nTgHSP70 对 PMs 的激活，而它抑制脂多糖对 PMs 的激活。用 rTgHSP70 预处理 WT 小鼠而非 TLR4 缺陷型小鼠的 PMs，会导致在用 rTgHSP70 再次刺激时 NO 释放受到抑制。同样，用 nTgHSP70 预处理 WT 小鼠而非 TLR4 缺陷型小鼠的 PMs，会导致在用 nTgHSP70 再次刺激时 NO 释放受到抑制。多粘菌素 B 不抑制 rTgHSP70 和 nTgHSP70 诱导的 TLR4 缺陷型小鼠 PMs 的耐受性。此外，WT 小鼠的 PMs 在经 rTgHSP70 再次刺激后细胞因子信号抑制因子 1（SOCS-1）表达增加，而 TLR4 缺陷型小鼠的 PMs 则不然。JNK 和 I-κBα 的磷酸化发生在 rTgHSP70 诱导的 TLR4 缺陷型小鼠 PMs 的耐受性中，但在 WT 小鼠的 PMs 中未发生。这些数据表明，TgHSP70 的信号传导机制由 TLR2、MyD88 和 IRAK4 介导，而非由 TLR4 介导。另一方面，TgHSP70 诱导的耐受性信号由 TLR4 介导，且 SOCS-1 的表达抑制了 TLR2 信号通路。
