Abstract

Cytokines are considered a promising immunotherapy for chronic diseases, because of their potency and fundamental roles in pathological processes. However, their therapeutic use is limited because of their poor pharmacokinetics and pleiotropic effects in various organs. These problems may be overcome by cell-specific delivery of the cytokine. This approach involves chemical modification of the protein with homing devices that recognize receptors on target cells. The cytokine interleukin-10 (IL10) may be valuable as a therapeutic cytokine for patients with liver cirrhosis. However, its rapid renal elimination and general immunosuppressive activities limit therapeutic use. We therefore aim to target this cytokine in the liver, in particular to fibrogenic hepatic stellate cells (HSCs). We show that IL10 is successfully modified with mannose 6-phosphate (M6P), which is a homing device for the mannose 6-phosphate/insulin-like growth factor II (M6P/IGFII) receptor expressed on activated HSCs. Chemical modification did not diminish IL10 efficacy with regard to in vitro anti-inflammatory (lipopolysaccharide-stimulated tumor necrosis factor α release) and antifibrotic (collagen deposition and degradation) activities. Biodistribution studies with radiolabeled M6P-IL10 and IL10 in rats with liver fibrosis showed that modification with M6P groups induced a shift in the distribution from the kidneys (IL10) to the liver (M6P-IL10). Hepatocellular binding of M6P-IL10 occurred via M6P/IGFII receptors and scavenger receptors, indicating that not only HSCs but also Kupffer and endothelial cells are target cells. IL10 did not bind to these receptors. We conclude that we prepared an active and liver-specific form of the cytokine IL10 that can be evaluated for its efficacy to treat liver diseases.