Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain.
Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain.
EMBO Mol Med. 2018 Jul;10(7). doi: 10.15252/emmm.201708403.
The protein kinase p38α plays a key role in cell homeostasis, and p38α signaling in intestinal epithelial cells protects against colitis-induced tumorigenesis. However, little is known on the contribution of p38α signaling in intestinal stromal cells. Here, we show that myeloid cell-specific downregulation of p38α protects mice against inflammation-associated colon tumorigenesis. The reduced tumorigenesis correlates with impaired detection in the colon of crucial chemokines for immune cell recruitment. We identify insulin-like growth factor-1 (IGF-1) as a novel mediator of the p38α pathway in macrophages. Moreover, using genetic and pharmacological approaches, we confirm the implication of IGF-1 produced by myeloid cells in colon inflammation and tumorigenesis. We also show a correlation between IGF-1 pathway activation and the infiltration of myeloid cells with active p38α in colon samples from patients with ulcerative colitis or colon cancer. Altogether, our results uncover an important role for myeloid IGF-1 downstream of p38α in colitis-associated tumorigenesis and suggest the interest in evaluating IGF-1 therapies for inflammation-associated intestinal diseases, taking into consideration IGF-1 signaling and immune cell infiltration in patient biopsies.
丝裂原活化蛋白激酶 p38α 在细胞内稳态中发挥着关键作用，其在肠道上皮细胞中的信号传递可预防结肠炎相关的肿瘤发生。然而，肠道基质细胞中 p38α 信号传递的作用却知之甚少。在这里，我们发现髓系细胞中 p38α 的特异性下调可保护小鼠免受炎症相关的结肠癌发生。肿瘤形成减少与在结肠中检测到免疫细胞募集的关键趋化因子受损相关。我们鉴定出胰岛素样生长因子-1（IGF-1）是巨噬细胞中 p38α 通路的一种新型介质。此外，我们通过遗传和药理学方法证实了髓系细胞产生的 IGF-1 在结肠炎症和肿瘤发生中的作用。我们还显示了在溃疡性结肠炎或结肠癌患者的结肠样本中，IGF-1 通路的激活与具有活性 p38α 的髓系细胞浸润之间存在相关性。总之，我们的研究结果揭示了髓系细胞中 p38α 下游的 IGF-1 在结肠炎相关肿瘤发生中的重要作用，并表明有必要评估 IGF-1 疗法在炎症相关的肠道疾病中的应用，同时考虑到患者活检中的 IGF-1 信号传递和免疫细胞浸润。
