Loss of the platelet activating factor receptor in mice augments PMA-induced inflammation and cutaneous chemical carcinogenesis
Loss of the platelet activating factor receptor in mice augments PMA-induced inflammation and cutaneous chemical carcinogenesis
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DOI：
10.1093/carcin/bgr322
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发表时间：
2012-03-01
期刊：
影响因子：
4.7
通讯作者：
Konger, Raymond L.
中科院分区：
文献类型：
--
作者：
Sahu, Ravi P.;Kozman, Amal A.;Konger, Raymond L.
虽然血小板活化因子（PAF）是一个众所周知的急性炎症介质，很少有人知道关于PAF在慢性炎症中的作用。已知佛波酯刺激PAF产生。此外，重复应用佛波醇酯诱导持续炎症反应的能力对其致瘤活性至关重要。因此，我们研究了PAF是否作为佛波酯诱导的炎症和肿瘤发生的介质。虽然PAF受体敲除小鼠（PAFR（-/-））显示出对佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）的急性炎症反应的预期但适度的减少，但这些小鼠在长期PMA应用后表现出令人惊讶的炎症增加。通过许多发现记录了这种炎症增加，包括：皮肤厚度增加、髓过氧化物酶活性和表达增加以及已知炎症介质的表达增加。有趣的是，媒介物处理的PAFR（-/-）小鼠也表现出炎症标志物水平的适度增加。这表明，血小板活化因子受体（PAFR）的作用，以抑制慢性炎症反应的其他刺激，如屏障破坏。慢性PAFR激活具有抗炎作用的观点通过重复局部PAFR激动剂给药导致皮肤中髓过氧化物酶活性降低而得到证实。我们接下来利用7，12-二甲基苯并（a）蒽/PMA致癌方案来证明PAFR（-/-）小鼠与野生型对照小鼠相比表现出显著增加的肿瘤形成和恶性进展。这些研究为PAFR的两个重要的、意想不到的和可能相互关联的病理作用提供了证据：首先，PAFR抑制PMA诱导的慢性炎症;其次，PAFR抑制化学致癌物引起的肿瘤发展。
Although platelet-activating factor (PAF) is a well-known acute inflammatory mediator, little is known regarding the role of PAF in chronic inflammation. Phorbol esters are known to stimulate PAF production. Moreover, the ability of repeated applications of phorbol esters to induce a sustained inflammatory response is crucial to their tumorigenic activity. We therefore examined whether PAF acts as a mediator of phorbol ester-induced inflammation and tumorigenesis. While PAF receptor knockout mice (PAFR (-/-)) showed an expected but modest reduction in the acute inflammatory response to phorbol 12-myristate 13-acetate (PMA), these mice exhibited a surprising increase in inflammation following chronic PMA application. This increased inflammation was documented by a number of findings that included: increased skin thickness, increased myeloperoxidase activity and expression and increased expression of known inflammatory mediators. Interestingly, vehicle-treated PAFR(-/-) mice also exhibited modest increases in levels of inflammatory markers. This suggests that the platelet activating factor receptor (PAFR) acts to suppress chronic inflammation in response to other stimuli, such as barrier disruption. The idea that chronic PAFR activation is anti-inflammatory was documented by repetitive topical PAFR agonist administration that resulted in reduced myeloperoxidase activity in skin. We next utilized a 7,12-dimethylbenz(a)anthracene/PMA carcinogenesis protocol to demonstrate that PAFR (-/-) mice exhibit significantly increased tumor formation and malignant progression compared with wild-type control mice. These studies provide evidence for two important, unexpected and possibly interrelated pathological roles for the PAFR: first, the PAFR acts to suppress PMA-induced chronic inflammation; secondly, the PAFR acts to suppress neoplastic development in response to chemical carcinogens.