Chemerin Isoform-Specific Effects on Hepatocyte Migration and Immune Cell Inflammation

Abstract

Murine chemerin is C-terminally processed to the bioactive isoforms, muChem-156 and muChem-155, among which the longer variant protects from hepatocellular carcinoma (HCC). However, the role of muChem-155 is mostly unknown. Here, we aimed to compare the effects of these isoforms on the proliferation, migration and the secretome of the human hepatocyte cell lines HepG2 and Huh7 and the murine Hepa1-6 cell line. Therefore, huChem-157 and -156 were overexpressed in the human cells, and the respective murine variants, muChem-156 and -155, in the murine hepatocytes. Both chemerin isoforms produced by HepG2 and Hepa1-6 cells activated the chemerin receptors chemokine-like receptor 1 (CMKLR1) and G protein-coupled receptor 1 (GPR1). HuChem-157 was the active isoform in the Huh7 cell culture medium. The potencies of muChem-155 and muChem-156 to activate human GPR1 and mouse CMKLR1 were equivalent. Human CMKLR1 was most responsive to muChem-156. Chemerin variants showed no effect on cell viability and proliferation. Activation of the mitogen-activated protein kinases Erk1/2 and p38, and protein levels of the epithelial–mesenchymal transition marker, E-cadherin, were not regulated by the chemerin variants. Migration was reduced in HepG2 and Hepa1-6 cells by the longer isoform. Protective effects of chemerin in HCC include the modulation of cytokines but huChem-156 and huChem-157 overexpression did not change IL-8, CCL20 or osteopontin in the hepatocytes. The conditioned medium of the transfected hepatocytes failed to alter these soluble factors in the cell culture medium of peripheral blood mononuclear cells (PBMCs). Interestingly, the cell culture medium of Huh7 cells producing the inactive variant huChem-155 reduced CCL2 and IL-8 in PBMCs. To sum up, huChem-157 and muChem-156 inhibited hepatocyte migration and may protect from HCC metastasis. HuChem-155 was the only human isoform exerting anti-inflammatory effects on immune cells.