Synthesis of IL-6 by Hepatocytes Is a Normal Response to Common Hepatic Stimuli

Abstract

Exogenous interleukin 6 (IL-6), synthesized at the initiation of the acute phase response, is considered responsible for signaling hepatocytes to produce acute phase proteins. It is widely posited that IL-6 is either delivered to the liver in an endocrine fashion from immune cells at the site of injury, or alternatively, in a paracrine manner by hepatic immune cells within the liver. A recent publication showed there was a muted IL-6 response in lipopolysaccharide (LPS)-injured mice when nuclear NFκB was specifically inactivated in the hepatocytes. This indicates hepatocellular signaling is also involved in regulating the acute phase production of IL-6. Herein, we present extensive in vitro and in vivo evidence that normal hepatocytes are directly induced to synthesize IL-6 mRNAs and protein by challenge with LPS, a bacterial hepatotoxin, and by HGF, an important regulator of hepatic homeostasis. As the IL-6 receptor is found on the hepatocyte, these results reveal that induction of the acute phase response can be regulated in an autocrine as well as endocrine/paracrine fashion. Further, herein we provide data indicating that following partial hepatectomy (PHx), HGF differentially regulates IL-6 production in hepatocytes (induces) versus immune cells (suppresses), signifying disparate regulation of the cell sources involved in IL-6 production is a biologically relevant mechanism that has previously been overlooked. These findings have wide ranging ramifications regarding how we currently interpret a variety of in vivo and in vitro biological models involving elements of IL-6 signaling and the hepatic acute phase response.

Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway

“…It is known that, in the liver, IL-6 is secreted by Kupffer cells and hepatocytes (35,36). IL-6 induces the production of acute-phase proteins during acute inflammation in the liver, and serum levels of IL-6 correlate positively with the severity of the disease (26).…”

Donor interleukin 6 gene polymorphisms predict the recurrence of hepatocellular carcinoma after liver transplantation

“…One possible explanation for these results is that the authors did not evaluate the role of donor gene polymorphisms in HCC recurrence [39]. Norris et al showed that hepatocytes could directly synthesize IL6 mRNAs and protein following hepatic stimuli, including partial hepatectomy [40]. Circulating tumor cells can lead to recurrence and metastasis of HCC after liver transplantation [41].…”

Immunological aspect of the liver and metastatic uveal melanoma

“…However, under inflammatory conditions some hepatocytes express MHC class II [30] and initiate an adoptive immune response. Hepatocytes produce IL-6 upon stimulation by HGF, lipopolysaccharide, or bacterial hepatotoxins [37] .…”