Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada.
Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada.
Immunol Res. 2018 Apr;66(2):245-254. doi: 10.1007/s12026-018-8987-6.
The prolactin-inducible protein (PIP) is considered a valuable biomarker that is associated with both benign and malignant pathological conditions of the mammary gland. The function of PIP in breast tumorigenesis remains unknown; however, evidence from our laboratory and others suggest that it regulates host immunity. Studies with PIP-deficient (PIP) mice demonstrated significantly lower numbers of CD4 T cells in their secondary lymphoid organs, impaired Th1 response, and impaired nitric oxide (NO) production. To further delineate the immunoregulatory role of PIP, we compared the expression of IFN-γR and TLR4, pro-inflammatory cytokine production, and intracellular signaling events by IFN-γ and lipopolysaccharide (LPS)-stimulated macrophages from wild-type (WT) and PIP mice. We showed that although the expressions of IFN-γR and TLR4 were comparable, productions of pro-inflammatory cytokines were decreased in PIP macrophages. This was associated with decreased phosphorylation of mitogen-activated protein kinase (MAPK) and signal transducer of activation of transcription (STAT) proteins in macrophages from PIP mice. Interestingly, the expression of suppressors of cytokine signaling (SOCS) 1 and 3 proteins, known to suppress IFN-γ and LPS signaling, was higher in PIP macrophages compared to those from WT mice. Collectively, our studies show that deficiency of PIP significantly affects intracellular signaling events leading to decreased pro-inflammatory cytokine production, and further confirms a role for PIP as an important immunoregulatory protein. This direct link between PIP and cell-mediated immunity, a key component of the immune system that is critical for cancer control, may have significant therapeutic implications.
泌乳素诱导蛋白（PIP）被认为是一种有价值的生物标志物，与乳腺的良性和恶性病理状况都有关联。PIP 在乳腺癌发生中的功能尚不清楚；然而，我们实验室和其他实验室的证据表明，它调节着宿主的免疫。用 PIP 缺陷（PIP）小鼠进行的研究表明，它们次级淋巴器官中的 CD4 T 细胞数量明显减少，Th1 反应受损，一氧化氮（NO）产生受损。为了进一步阐明 PIP 的免疫调节作用，我们比较了野生型（WT）和 PIP 小鼠的巨噬细胞中 IFN-γR 和 TLR4 的表达、促炎细胞因子的产生以及 IFN-γ 和脂多糖（LPS）刺激后的细胞内信号转导事件。我们表明，尽管 IFN-γR 和 TLR4 的表达相当，但 PIP 巨噬细胞中促炎细胞因子的产生减少。这与 PIP 小鼠巨噬细胞中丝裂原活化蛋白激酶（MAPK）和转录激活因子（STAT）蛋白的磷酸化减少有关。有趣的是，抑制细胞因子信号（SOCS）1 和 3 蛋白的表达，已知这些蛋白会抑制 IFN-γ 和 LPS 信号，在 PIP 巨噬细胞中比 WT 小鼠中的表达更高。总之，我们的研究表明，PIP 的缺乏显著影响细胞内信号转导事件，导致促炎细胞因子产生减少，并进一步证实 PIP 作为一种重要的免疫调节蛋白的作用。PIP 与细胞介导的免疫之间的这种直接联系，是免疫系统的一个关键组成部分，对癌症控制至关重要，可能具有重要的治疗意义。
