Differential COX-2 induction by viral and bacterial PAMPs: Consequences for cytokine and interferon responses and implications for anti-viral COX-2 directed therapies.
Differential COX-2 induction by viral and bacterial PAMPs: Consequences for cytokine and interferon responses and implications for anti-viral COX-2 directed therapies.
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DOI：
10.1016/j.bbrc.2013.07.006
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发表时间：
2013-08-23
影响因子：
3.1
通讯作者：
Mitchell, Jane A.
中科院分区：
文献类型：
--
作者：
Kirkby, Nicholas S.;Zaiss, Anne K.;Wright, William R.;Jiao, Jing;Chan, Melissa V.;Warner, Timothy D.;Herschman, Harvey R.;Mitchell, Jane A.
我们报告了 Toll 样受体 (TLR) 与体内 COX 酶的相互作用。 COX-2 广泛由 LPS (TLR4) 诱导，但更局部由聚 (I:C) (TLR3) 诱导。 COX-1/2 缺失以 TLR 特异性方式改变了对 TLR 激活的反应。 COX-2 缺失增强了干扰素对病毒型 TLR3/7/9 配体的反应。 COX-2抑制可以提供一种新的抗病毒治疗策略。环加氧酶 2 (COX)-2 由细菌和病毒感染诱导，在抗病原体免疫中具有复杂且人们知之甚少的作用。在这里，我们使用敲入荧光素酶报告模型对小鼠中一系列组织中的 Cox2 表达进行成像，这些小鼠经过典型细菌病原体相关分子模式 (PAMP)、LPS（激活 Toll 样受体 (TLR)4）或聚 (I:C)（一种病毒 PAMP，激活 TLR3）治疗。 LPS 在所有检查的组织中诱导 Cox2 表达。相比之下，聚 (I:C) 引起的反应较温和，仅限于一部分组织。在用 LPS、poly(I:C)、MALP2 (TLR2/6)、Pam3CSK4 (TLR2/1)、R-848 (TLR7/8) 或 CpG ODN (TLR9) 处理的野生型、Cox1−/− 和 Cox2−/− 小鼠血浆中测量一组细胞因子和干扰素，以确定每种 COX 亚型是否/如何调节特定的 PAMP/TLR 反应。只有 LPS 才会导致小鼠状况显着下降（不活动、驼背、立毛）。然而，所有 TLR 激动剂都会产生细胞因子反应，其中许多细胞因子反应通过 Cox1 或 Cox2 基因缺失以特定方式调节。值得注意的是，我们观察到 Cox2 基因缺失对细菌 PAMP、LPS 和病毒 PAMP、poly(I:C) 的反应产生相反的影响，这与 PAMP 诱导 Cox2 表达的不同能力一致。 Cox2基因缺失限制了LPS产生的血浆IL-1β和干扰素-γ反应以及低体温。相反，在对poly(I:C)的反应中，Cox2−/−小鼠表现出增强的血浆干扰素（IFNα、β、γ、λ）和相关细胞因子反应（IP-10、IL-12）。这些观察结果表明，在感染早期给予COX-2选择性抑制剂可以增强和/或延长内源性干扰素反应，从而增强抗病毒免疫力。
We report interactions of Toll-like receptors (TLRs) with COX enzymes in vivo. COX-2 was broadly induced by LPS (TLR4) but more locally by poly(I:C) (TLR3). COX-1/2 deletion modified the response to TLR activation in a TLR-specific manner. COX-2 deletion enhanced interferon responses to viral-type TLR3/7/9 ligands. COX-2 inhibition could provide a novel anti-viral therapeutic strategy. Cyclooxygenase 2 (COX)-2 is induced by bacterial and viral infections and has complex, poorly understood roles in anti-pathogen immunity. Here, we use a knock-in luciferase reporter model to image Cox2 expression across a range of tissues in mice following treatment with the either the prototypical bacterial pathogen-associated molecular pattern (PAMP), LPS, which activates Toll-like receptor (TLR)4, or with poly(I:C), a viral PAMP, which activates TLR3. LPS induced Cox2 expression in all tissues examined. In contrast, poly(I:C) elicited a milder response, limited to a subset of tissues. A panel of cytokines and interferons was measured in plasma of wild-type, Cox1−/− and Cox2−/− mice treated with LPS, poly(I:C), MALP2 (TLR2/6), Pam3CSK4 (TLR2/1), R-848 (TLR7/8) or CpG ODN (TLR9), to establish whether/how each COX isoform modulates specific PAMP/TLR responses. Only LPS induced notable loss of condition in mice (inactivity, hunching, piloerection). However, all TLR agonists produced cytokine responses, many of which were modulated in specific fashions by Cox1 or Cox2 gene deletion. Notably we observed opposing effects of Cox2 gene deletion on the responses to the bacterial PAMP, LPS, and the viral PAMP, poly(I:C), consistent with the differing abilities of the PAMPs to induce Cox2 expression. Cox2 gene deletion limited the plasma IL-1β and interferon-γ responses and hypothermia produced by LPS. In contrast, in response to poly(I:C), Cox2−/− mice exhibited enhanced plasma interferon (IFNα,β,γ,λ) and related cytokine responses (IP-10, IL-12). These observations suggest that a COX-2 selective inhibitor, given early in infection, may enhance and/or prolong endogenous interferon responses, and thereby increase anti-viral immunity.
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