An Essential Role of Th1 Responses and Interferon-gamma in Infection-Mediated Suppression of Neoplastic Growth
An Essential Role of Th1 Responses and Interferon-gamma in Infection-Mediated Suppression of Neoplastic Growth
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DOI：
10.4161/cbt.2.6.557
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发表时间：
2003-08
影响因子：
3.6
通讯作者：
E. Rankin;Duonan Yu;Jiu Jiang;Hao Shen;E. Pearce;M. Goldschmidt;David E. L evy;T. Golovkina;C. Hunter;A. Thomas-Tikhonenko
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文献类型：
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作者：
E. Rankin;Duonan Yu;Jiu Jiang;Hao Shen;E. Pearce;M. Goldschmidt;David E. L evy;T. Golovkina;C. Hunter;A. Thomas-Tikhonenko
我们之前已经证明，在小鼠中，急性弓形虫感染会导致血管生成的全身性抑制，从而强烈抑制肿瘤生长。在这里，我们研究了Th1细胞因子，特别是干扰素γ(IFNG)在这一现象中的作用。除了弓形虫，在急性感染其他Th1反应诱导病原体时，肿瘤生长很容易被阻止，如李斯特菌和淋巴细胞性脉络膜脑膜炎病毒(LCMV)。相反，慢性感染LCMV(Th1反应被强烈抑制)和急性感染曼氏血吸虫(Th2反应占优势)没有提供抗肿瘤保护。为了证实Th1细胞因子参与感染介导的抑制肿瘤生长，我们利用了缺乏白介素10(IL10)的小鼠，白介素10是Th1反应的抑制因子。当用B16细胞攻击并伴有弓形虫感染时，IL10缺失和野生型小鼠都表现出对肿瘤生长的抵抗力。然而，IL10缺失的动物所携带的肿瘤甚至比野生型动物所携带的肿瘤更小。这种增强的抵抗力与循环中主要的Th1细胞因子IFNG水平的显著升高有关。此外，尽管白介素12和肿瘤坏死因子g对于肿瘤抑制是不必要的，但在缺乏IFNG产生或信号的动物中，肿瘤生长和新生血管显著增强。有趣的是，这种增强在未感染的动物中也很明显，这表明IFNG及其抗血管生成作用是感染依赖和独立肿瘤监测的基础。
We had previously demonstrated that in mice acute toxoplasmosis leads to systemic inhibition of angiogenesis and, consequently, strong suppression of neoplastic growth. Here we investigated the role of Th1 cytokines, in particular interferon gamma (IFNg), in this phenomenon. Besides toxoplasma, neoplastic growth was readily blocked during acute infection with other Th1 response-inducing pathogens such as Listeria monocytogenes and lymphocytic choriomeningitis virus (LCMV). In contrast, chronic infection with LCMV (when Th1 responses were strongly suppressed) and acute infection with Schistosoma mansoni (when Th2 responses predominated) afforded no anti-tumor protection. To corroborate the involvement of Th1 cytokines in infection-mediated suppression of neoplastic growth, we utilized mice deficient in interleukin-10 (IL10), a suppressor of Th1 responses. When challenged with B16 cells concomitantly with toxoplasma infection, both IL10-null and wild type mice exhibited resistance to neoplastic growth. However, tumors borne by IL10-null animals were even smaller than those borne by their wild type counterparts. This enhanced resistance correlated with dramatically elevated levels of circulating IFNg, a principal Th1 cytokine. Furthermore, while interleukin-12 and tumor necrosis factor g were dispensable for tumor suppression, in animals deficient in IFNg production or signaling, tumor growth and neovascularization were markedly enhanced. Interestingly, the enhancement was also apparent in uninfected animals suggesting that IFNg and its anti-angiogenic effects underlie both infection-dependent and -independent tumor surveillance.