Abstract
The chemokine chemerin exists as C-terminally processed isoforms whose biological functions are mostly unknown. A highly active human chemerin variant (huChem-157) was protective in experimental hepatocellular carcinoma (HCC) models. Hepatic stellate cells (HSCs) are central mediators of hepatic fibrogenesis and carcinogenesis and express the chemerin receptors chemokine-like receptor 1 (CMKLR1) and G protein-coupled receptor 1 (GPR1). Here we aimed to analyse the effect of chemerin isoforms on the viability, proliferation and secretome of the human HSC cell line LX-2. Therefore, huChem-157, 156 and 155 were over-expressed in LX-2 cells, which have low endogenous chemerin levels. HuChem-157 produced in LX-2 cells activated CMKLR1 and GPR1, and huChem-156 modestly induced GPR1 signaling. HuChem-155 is an inactive chemerin variant. Chemerin isoforms had no effect on cell viability and proliferation. Cellular expression of the fibrotic proteins galectin-3 and alpha-smooth muscle actin was not regulated by any chemerin isoform. HuChem-156 increased IL-6, IL-8 and galectin-3 in cell media. HuChem-157 was ineffective, and accordingly, did not enhance levels of these proteins in media of primary human hepatic stellate cells when added exogenously. These analyses provide evidence that huChem-156 is the biologic active chemerin variant in hepatic stellate cells and acts as a pro-inflammatory factor.
Highlights
Chemerin is a multifunctional protein with high expression in adipocytes and hepatocytes [1]
G Protein-Coupled Receptor 1 (GPR1) mRNA was highly abundant in the stromal vascular cell fraction, which is composed of fibroblasts, mesenchymal stem cells, endothelial cells, as well as smooth muscle cells and macrophages [8,9]
LX-2 cells were transfected with the recombinant plasmids to overexpress chemerin variants
Summary
Chemerin is a multifunctional protein with high expression in adipocytes and hepatocytes [1]. Chemokine-like receptor 1 (CMKLR1) and G Protein-Coupled Receptor 1 (GPR1) are functional chemerin receptors [2,3]. CMKLR1 is expressed by various tissues and cells including cells of the innate and adaptive immune system [4]. According to the Human Protein Atlas, GPR1 mRNA was hardly detectable in immune cells [5] and a separate study could not identify GPR1 mRNA in macrophages [6]. In murine peritoneal exudate cells, GPR1 mRNA was 0.02 to 0.03% of CMKLR1 mRNA levels [7]. GPR1 mRNA was highly abundant in the stromal vascular cell fraction, which is composed of fibroblasts, mesenchymal stem cells, endothelial cells, as well as smooth muscle cells and macrophages [8,9]. Chemerin is a well described chemoattractant and can act via both receptors to stimulate chemotaxis of immune or non-immune cells [1,10,11,12]
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