Reithmeier-Rost Dagmar, Bierschenk Suse, Filippova Natalia, Schröder-Braunstein Jutta, Sing Andreas
Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität München, Pettenkoferstrasse 9a, 80336 München, Germany.
Cell Immunol. 2004 Sep-Oct;231(1-2):63-74. doi: 10.1016/j.cellimm.2004.12.003. Epub 2005 Jan 7.
The virulence antigen (LcrV) of pathogenic yersiniae "silences" macrophages against stimulation with the TLR2-agonist zymosan A in a CD14/TLR2-dependent fashion via IL-10 induction. This pathogenically important "silencing" resembles TLR tolerance phenomena; in these, pre-exposure to a primary tolerizing TLR-agonist renders macrophages unresponsive to stimulation with a secondary challenging TLR-agonist which may involve either the same (TLR homotolerance) or a different TLR (TLR heterotolerance) as the primary TLR-agonist. Here, we show that rLcrV induces TLR homo- and heterotolerance against TLR2- or TLR4-agonists both in human and murine macrophages, respectively. The underlying mechanism of LcrV-induced tolerance is most likely not due to changes in TLR2- or TLR4 expression, but involves LcrV-mediated IL-10 production, since LcrV-induced TLR homo- and heterotolerance is highly impaired in IL-10(-/-) macrophages. Moreover, the involvement of IL-10 in TLR tolerance induction seems to be a more general phenomenon as shown by experiments using different TLR-agonists in IL-10(-/-) macrophages. Since LcrV acts as a secreted protein upon macrophages without requiring direct cell contact, as shown in transwell assays, we propose that yersiniae exploit IL-10-involving TLR tolerance mechanisms by the virulence factor LcrV.
致病性耶尔森菌的毒力抗原（LcrV）通过诱导白细胞介素-10，以CD14/TLR2依赖的方式“沉默”巨噬细胞，使其对TLR2激动剂酵母聚糖A的刺激无反应。这种在致病方面很重要的“沉默”类似于TLR耐受现象；在这些现象中，预先接触一种主要的耐受诱导性TLR激动剂会使巨噬细胞对第二种具有挑战性的TLR激动剂的刺激无反应，这第二种激动剂可能与第一种TLR激动剂相同（TLR同型耐受）或不同（TLR异型耐受）。在此，我们表明重组LcrV分别在人和鼠巨噬细胞中诱导对TLR2或TLR4激动剂的TLR同型和异型耐受。LcrV诱导耐受的潜在机制很可能不是由于TLR2或TLR4表达的变化，而是涉及LcrV介导的白细胞介素-10的产生，因为在白细胞介素-10基因敲除（IL-10-/-）的巨噬细胞中，LcrV诱导的TLR同型和异型耐受受到严重损害。此外，如在IL-10-/-巨噬细胞中使用不同TLR激动剂的实验所示，白细胞介素-10参与TLR耐受诱导似乎是一种更普遍的现象。由于如在transwell实验中所示，LcrV作为一种分泌蛋白作用于巨噬细胞，无需直接细胞接触，我们提出耶尔森菌通过毒力因子LcrV利用涉及白细胞介素-10的TLR耐受机制。
