CXCL9 Contributes To Chemotherapy-Induced Acute Intestinal Damage Through Proliferative Inhibition Of Epithelial Cells

Apart from angiostasis and chemoattraction, CXCL9 can derange hematopoiesis by its influence on mesenchymal stroma cells. The receptor of CXCL9, CXCR3, is abundantly expressed intracellularly in epithelial cells, even though it is rarely present on the surface of these cells. Here, we hypothesized that CXCL9 influences the proliferative and degenerative activity of epithelial cells in vitro and in vivo. CXCL9 inhibited the proliferation of MCF10A cells in a dose-dependent manner. In vivo, rhCXCL9 caused an intestinal weight loss of 30% in normal mice (n=6, 0.59±0.05 g of rhCXCL9 treated mice versus 0.83±0.06 g controls, P = 0.0007 determined by 2-tailed student’s t-test). Intestinal epithelial cells of 5-Fluorouracil (5-FU) treated mice developed a 2.55 fold higher level of cxcl9 expression, indicating that CXCL9 may participate in a chemotherapy-induced damage of the intestinal epithelium. Neutralization of the up-regulated endogenous CXCL9 by anti-CXCL9 monoclonal antibodies accelerated epithelial regeneration determined by villi length (317.5±19.9 μm versus no-antibody control 283.7±17.1 μm, P < 0.001) and crypt depth (78.0±8 μm versus control 67.9±10.9 μm, P = 0.326). CXCL9 function was highly associated with p70 ribosomal S6 kinase (p70S6K) activation (50.0±2.2 MFI versus control 27.9±1.4 MFI, P = 0.007), which was reversed by anti-CXCR3 (31.4±5.7 MFI, n=4). CXCL9 downstreamingly stimulated TGF-β secretion of epithelial cells through the mTOR/p70S6K pathway (66.3±17.1 pg/mL versus on-treated control 39.8±12.2 pg/mL, P <0.05), which was reversed by anti-CXCR3 (46.8±21.6 pg/mL, n=8). That explains the anti-proliferative effect of CXCL9 on these cells. Our results strongly suggest that anti-CXCL9 may help to mitigate a chemotherapy-induced intestinal damage. The work was supported by the National Science Foundation China (81273576, 30801419, 30901873), and the German Academic Exchange Service (A/09/90104).