Howe Cody S, Beswick Ellen J
Division of Digestive Diseases and Nutrition, Department of Internal Medicine, University of Kentucky, Lexington, KY 40506, USA.
Cells. 2025 Jul 5;14(13):1031. doi: 10.3390/cells14131031.
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by bile duct inflammation and fibrosis, leading to cirrhosis and liver failure. Current therapies are limited to symptom management, with no approved treatments targeting fibrosis. We have identified the MAP kinase-activated protein kinase 2 (MK2) pathway as a potential therapeutic target for treating PSC due to its role in promoting inflammatory cytokine production and activation of fibroblasts. Thus, MDR2 knockout mice were treated therapeutically with MK2 inhibitors, which led to significantly reduced hepatic inflammation and fibrosis. Liver enzymes, collagen 1A1, and fibronectin were decreased in serum with MK2 inhibitor treatment. Furthermore, the production of IL-6, TNFα, CXCL5, collagen 1A1, and fibronectin was decreased in liver tissues and liver stellate cells, whereas the production of IL-10, G-CSF, and IL-22 was increased. MDR2KO mice treated with IL-22 also showed improvements in inflammation and fibrosis, along with increased IL-10 and G-CSF production. Taken together, we identified both a direct mechanism of MK2 regulation of fibrotic factors and an indirect cytokine-mediated mechanism whereby the levels of IL-22, IL-10, and G-CSF were increased with MK2 inhibition and contributed to decreased levels of fibrotic factors. These data suggest that the MK2 pathway is a promising treatment target for PSC.
原发性硬化性胆管炎（PSC）是一种慢性肝病，其特征为胆管炎症和纤维化，可导致肝硬化和肝衰竭。目前的治疗方法仅限于症状管理，尚无获批的针对纤维化的治疗方法。我们已确定丝裂原活化蛋白激酶激活的蛋白激酶2（MK2）通路是治疗PSC的潜在治疗靶点，因为它在促进炎性细胞因子产生和成纤维细胞活化中起作用。因此，用MK2抑制剂对MDR2基因敲除小鼠进行治疗，可显著减轻肝脏炎症和纤维化。MK2抑制剂治疗后，血清中的肝酶、胶原蛋白1A1和纤连蛋白水平降低。此外，肝脏组织和肝星状细胞中白细胞介素-6（IL-6）、肿瘤坏死因子α（TNFα）、CXC趋化因子配体5（CXCL5）、胶原蛋白1A1和纤连蛋白的产生减少，而白细胞介素-10（IL-10）、粒细胞集落刺激因子（G-CSF）和白细胞介素-22（IL-22）的产生增加。用IL-22治疗的MDR2基因敲除小鼠在炎症和纤维化方面也有改善，同时IL-10和G-CSF的产生增加。综上所述，我们确定了MK2调节纤维化因子的直接机制以及间接的细胞因子介导机制，即MK2抑制后IL-22、IL-10和G-CSF水平升高，并导致纤维化因子水平降低。这些数据表明，MK2通路是PSC有前景的治疗靶点。
