The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7- and TLR8-independent fashion
The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7- and TLR8-independent fashion
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DOI：
10.1038/sj.jid.5700286
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发表时间：
2006-06-01
影响因子：
6.5
通讯作者：
Klotz, Karl-Norbert
中科院分区：
文献类型：
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作者：
Schoen, Michael P.;Schoen, Margarete;Klotz, Karl-Norbert
咪喹莫特是咪唑喹啉家族的一种小分子免疫反应调节剂，在体外和体内临床应用中均显示出深刻的抗肿瘤和抗病毒功效。已经证明，这种活性是通过toll样受体（TLR）7-和tlr8信号级联介导的，导致促炎细胞因子的分泌，并连续诱导肿瘤导向的细胞免疫反应。此外，咪喹莫特对肿瘤细胞有直接的促凋亡作用。我们在这里证明，在TLR7和TLR8缺失的情况下，咪喹莫特诱导转录因子NF-kappa B的激活和下游促炎细胞因子的产生。在稳定转染了人腺苷受体亚型的中国仓鼠卵巢细胞中，我们在放射配体结合竞争实验中发现，咪喹莫特在与临床环境相关的浓度下与腺苷受体结合，与A(1)和A（2A）亚型的亲和力最高。对受体介导的腺苷酸环化酶激活的影响也进行了研究，这些实验表明咪喹莫特具有腺苷受体拮抗剂的作用。此外，咪喹莫特对受体下游腺苷酸环化酶活性有抑制作用。最后，利用转化的人角质形成细胞，我们提供了实验证据，证明咪喹莫特和A2A腺苷受体特异性化合物在缺乏免疫细胞的情况下类似地诱导促炎细胞因子。因此，咪喹莫特似乎抑制了一个重要的炎症反馈机制，通过拮抗腺苷受体依赖性cAMP的增加和伴随的受体非依赖性cAMP产生的抑制。这些新机制可能与促炎细胞因子的正向诱导协同作用，并且至少在一定程度上可以解释在一些患者体内观察到的深度炎症。
Imiquimod, a small-molecule immune response modifier of the imidazoquinoline family, has shown profound antitumoral and antiviral efficacy both in vitro and in clinical applications in vivo. It has been demonstrated that this activity is mediated through the Toll-like receptor (TLR)7- and TLR8-signaling cascade resulting in the secretion of proinflammatory cytokines and, consecutively, induction of a tumor-directed cellular immune response. In addition, imiquimod exerts a direct proapoptotic activity in tumor cells. We demonstrate here that imiquimod induces activation of the transcription factor NF-kappa B and the downstream production of proinflammatory cytokines in the absence of TLR7 and TLR8. In Chinese hamster ovary cells stably transfected with the human adenosine receptor subtypes, we then show in radioligand-binding competition experiments that imiquimod binds to adenosine receptors at concentrations relevant in clinical settings, with highest affinities to the A(1) and A(2A) subtypes. The effect on the receptor-mediated activation of adenylyl cyclase was also studied, and these experiments revealed that imiquimod acts as an adenosine receptor antagonist. In addition, imiquimod had an inhibitory effect on adenylyl cyclase activity downstream from the receptor. Finally, using transformed human keratinocytes, we provide experimental evidence that imiquimod and A2A adenosine receptor-specific compounds similarly induce proinflammatory cytokines in the absence of immune cells. Thus, imiquimod appears to suppress an important feedback mechanism of inflammation by antagonism of adenosine receptor-dependent increase of cAMP and a concomitant receptor-independent inhibition of cAMP production. These novel mechanisms presumably act synergistic with the positive induction of proinflammatory cytokines and can, at least in part, explain the profound inflammation observed in some patients in vivo.