Safety Assessment, Genentech, Inc., South San Francisco, CA 94080, USA.
Safety Assessment, Genentech, Inc., South San Francisco, CA 94080, USA.
Toxicol Appl Pharmacol. 2021 May 1;418:115494. doi: 10.1016/j.taap.2021.115494. Epub 2021 Mar 13.
Tumor progression locus 2 (Tpl2, gene name MAP3K8), a mitogen-activated protein kinase, is widely expressed in immune and non-immune cells to integrate tumor necrosis factor (TNF), toll-like receptors (TLRs), and interleukin-1 (IL1) receptor signaling to regulate inflammatory response. Given its central role in inflammatory response, Tpl2 is an attractive small molecule drug target. However, the role of Tpl2 as an oncogene or tumor suppressor gene remains controversial, and its function outside immune cells is not understood. We therefore utilized a Tpl2 kinase dead (Tpl2-KD) mouse model in an 18-month aging study to further elucidate Tpl2 effects on lifespan and chronic disease. Histopathological studies revealed the incidence and severity of spontaneous tumors and non-neoplastic lesions were comparable between wild type and Tpl2-KD mice. The only finding was that male Tpl2-KD mice had higher bodyweight and an increased incidence of liver steatosis, suggesting a sex-specific role for Tpl2 in hepatic lipid metabolism. In conclusion, loss of Tpl2 kinase activity did not lead to increased tumorigenesis over aging in mice but affected likely alterations in lipid metabolism in male animals.
肿瘤进展基因座 2（Tpl2，基因名称 MAP3K8）是一种丝裂原活化蛋白激酶，广泛存在于免疫细胞和非免疫细胞中，可整合肿瘤坏死因子（TNF）、Toll 样受体（TLRs）和白细胞介素-1（IL1）受体信号，从而调节炎症反应。鉴于其在炎症反应中的核心作用，Tpl2 是一个有吸引力的小分子药物靶点。然而，Tpl2 作为癌基因或肿瘤抑制基因的作用仍存在争议，其在免疫细胞外的功能尚不清楚。因此，我们利用 Tpl2 激酶缺失（Tpl2-KD）小鼠模型进行了为期 18 个月的衰老研究，以进一步阐明 Tpl2 对寿命和慢性疾病的影响。组织病理学研究显示，野生型和 Tpl2-KD 小鼠自发性肿瘤和非肿瘤病变的发生率和严重程度相当。唯一的发现是雄性 Tpl2-KD 小鼠体重更高，肝脂肪变性的发生率增加，提示 Tpl2 在肝脏脂质代谢中具有性别特异性作用。总之，Tpl2 激酶活性缺失并未导致小鼠衰老过程中肿瘤发生率增加，但可能影响了雄性动物的脂质代谢变化。
