IFN-lambda signal transduction

我们的研究表明，IFN-λ/IL-28维持了信号的激活， 转录转导子和转录激活子（STAT）1和STAT 2持续超过8小时。这是 这与由I型IFN激活的这些相同STAT的激活分布相反。 我们已经在人2fTGH纤维肉瘤和HaCat永生化皮肤角质形成细胞中证明了这一点。 细胞系和B16小鼠黑素瘤细胞系中。此外，IFN-λ上级优于 IFN-α在HaCat中诱导抗增殖作用，其抑制了 IFN-α处理未检测到凋亡细胞。与...形成鲜明对比 IFN-α，生化分析显示IFN-λ抑制STAT 1的激活， 不需要新的蛋白质合成。虽然两种干扰素都能对肿瘤细胞产生抗增殖作用， 我们的研究表明，这两种细胞因子在肿瘤细胞中不激活Jak/STAT通路， 同样的方式。为了比较IFN-λ的体内抗肿瘤作用，使用人 在异种移植肿瘤模型中，我们用IFN-β或IFN-γ治疗免疫受损的RagKO小鼠。 通过注射人IFN-λ诱导的携带IFN-λ的已建立的皮下肿瘤 角化细胞表达致癌Ras。每种细胞因子单独抑制进一步的肿瘤 增长然而，IFN-β在缩小已建立的肿瘤大小方面更有效。 我们正在进行的工作是同时使用这两种细胞因子，并确定它们的抗肿瘤作用是否可以 在组合使用时会增加。这些初步发现凸显了 IFN-λ在治疗癌症中的治疗用途。我们的研究与其他报告不同 因为我们使用重组蛋白而不是肿瘤细胞， IFN-λ。现在我们正在通过研究和比较IFN-λ和IFN-α来扩展这项工作 通过首先检测IFN诱导的STAT激活，在配对的原发性和几个 转移性黑色素瘤细胞系来源于同一患者。迄今为止， 来自3个不同患者的黑素瘤肿瘤仅对IFN-α有反应，而对IFN-λ无反应，因此 提示这些肿瘤可能不表达IFN-λ受体。令人惊讶的是，虽然所有 转移性肿瘤对IFN-α有反应，只有一些获得了对IFN-λ的反应性。从 在这项初步研究中，我们得出以下观察结果：（1）转移性肿瘤， 对IFN-λ的应答也必须对IFN-α/β应答;（2）表面IFN-λ受体 可能被甲基化或沉默，但可以在转移性肿瘤上表达， 一旦我们有了FACS抗体来测量这种受体的表达， （3）转移性黑素瘤对I型和III型干扰素的反应是异质性的。 因此，患者可能受益于在其癌症治疗中包括IFN-λ。

Our studies show that IFN-lambda/IL-28 sustains the activation of the signal transducers and activators of transcription (STAT)1 and STAT2 for longer than 8 hours. This is in contrast from the activation profile of these same STATs that are activated by type I IFNs. We have shown this in the human 2fTGH fibrosarcoma and HaCat immortalized skin keratinocyte cell lines and in B16 mouse melanoma cell line. In addition, IFN-lambda was superior than IFN-alpha in inducing an antiproliferative effect in HaCat, which paralleled detection of apoptotic cells that were not detected with IFN-alpha treatment. In stark contrast with IFN-alpha, biochemical analysis revealed that maintainance of STAT1 activation by IFN-lambda did not require new protein synthesis. Although both IFNs exert an antiproliferative effect on tumor cells, our study shows how these two cytokines do not activate the Jak/STAT pathway in the same manner. To compare the invivo antitumor effects of IFN-lambda, using a human xenograft tumor model, we have treated immunocompromised RagKO mice with either IFN-beta or IFN-lambda carrying established subcutaneous tumors induced by injecting them with human keratinocyte cells expressing oncogenic Ras. Each cytokine alone inhibited further tumor growth. However, IFN-beta was more efficient in shrinking the size of the established tumors. Our ongoing work is to use both cytokines together and determine if their antitumor effect can be augmented when used in combination. These initial findings highlight the potential therapeutic use of IFN-lambda in the treatment of cancer. Our study differs from other reports as we employed recombinant protein rather than tumor cells genetically engineered to secret IFN-lambda. Now we are expanding this work by studying and comparing IFN-lambda to IFN-alpha responsiveness by first detecting IFN-induced STAT activation in paired primary and several metastatic melanoma cell lines that were derived from the same patient. Thus far primary melanoma tumors from 3 different patients only respond to IFN-alpha but not to IFN-lambda thus suggesting that these tumors may not express IFN-lambda receptors. Surprisingly, while all metastatic tumors respond to IFN-alpha, only some gained responsiveness to IFN-lambda. From this initial study, we conclude with the following observations: (1) metastatic tumors that respond to IFN-lambda must also respond to IFN-alpha/beta; (2) Surface IFN-lambda receptors might be methylated or silenced but can be expressed on metastatic tumors-an observation that we will validate once we have FACS antibodies to measure expression of this receptor and (3)metastatic melatoma tumors are heterogeneous in their response to type I and type III IFNs. Therefore, patients may benefit from including IFN-lambda in their cancer treatment.