Production of IL‐6 by hepatocytes as a general response to injury

Abstract

IL‐6 is synthesized during the general acute phase response and, the hepatic response to IL‐6 is thought to be paracrine. For general injuries, provision of IL‐6 to the liver is thought to occur via NFkappaB‐dependent synthesis and release from immune cells at the injury site; IL‐6 is discharged into the circulation, travels to the liver, and stimulates the hepatocytes. When the site of injury is the liver itself, the IL‐6 is thought to be provided by resident hepatic immune cells. As LPS injection is used to simulate systemic bacterial infections, it was surprising to note that mice with hepatocellular‐specific inactivation of NFkappaB have significantly lower hepatic IL‐6 transcripts following LPS injection. Consequently, we hypothesized that hepatocytes can also synthesize IL‐6 in response to injury. Herein, we provide irrefutable evidence that normal hepatocytes in serum‐free cultures are capable of producing both IL‐6 mRNA and protein. Furthermore, injection of LPS into animals leads to production of hepatocellular IL‐6 and, hepatocytes from regenerating livers synthesize IL‐6 following hepatic resection. Finally we demonstrate that, HGF, an important monitor of hepatic function, regulates IL‐6 production by the hepatocytes both in vitro and in vivo. Combined, these results indicate that production of acute phase proteins in response to general injury can be autocrine.