Lehner M D, Morath S, Michelsen K S, Schumann R R, Hartung T
Biochemical Pharmacology, University of Konstanz, Konstanz, Germany.
J Immunol. 2001 Apr 15;166(8):5161-7. doi: 10.4049/jimmunol.166.8.5161.
Exposure of macrophages to LPS induces a state of hyporesponsiveness to subsequent stimulation with LPS termed LPS desensitization or tolerance. To date, it is not known whether similar mechanisms of macrophage refractoriness are induced on contact with components of Gram-positive bacteria. In the present study, we demonstrate that pretreatment with highly purified lipoteichoic acid (LTA) results in suppression of cytokine release on restimulation with LTA in vitro and in vivo in both C3H/HeN and C3H/HeJ mice, but not in macrophages from Toll-like receptor (TLR)-2-deficient mice. Furthermore, desensitization in response to LPS or LTA exposure also inhibits responses to the other stimulus ("cross-tolerance"), suggesting that signaling pathways shared by TLR2 and TLR4 are impaired during tolerance. Finally, we show that LPS- or LTA-induced cross-tolerance is not transferred to hyporesponsive cells cocultured with LPS/LTA-responsive macrophages, showing that soluble mediators do not suffice for tolerance induction in neighboring cells.
巨噬细胞暴露于脂多糖（LPS）会诱导一种对随后LPS刺激反应性降低的状态，称为LPS脱敏或耐受。迄今为止，尚不清楚巨噬细胞与革兰氏阳性菌成分接触时是否会诱导类似的不应性机制。在本研究中，我们证明，用高度纯化的脂磷壁酸（LTA）预处理会导致C3H/HeN和C3H/HeJ小鼠在体外和体内再次用LTA刺激时细胞因子释放受到抑制，但在Toll样受体（TLR）-2缺陷小鼠的巨噬细胞中未出现这种情况。此外，对LPS或LTA暴露的脱敏反应也会抑制对另一种刺激的反应（“交叉耐受”），这表明TLR2和TLR4共有的信号通路在耐受过程中受损。最后，我们表明，LPS或LTA诱导的交叉耐受不会转移到与LPS/LTA反应性巨噬细胞共培养的低反应性细胞中，这表明可溶性介质不足以诱导邻近细胞产生耐受。
