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

PLOS ONE, Dec 2019

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.

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

et al. (2014) Synthesis of IL-6 by Hepatocytes Is a Normal Response to Common Hepatic Stimuli. PLoS ONE 9(4): e96053. doi:10.1371/journal.pone.0096053 Synthesis of IL-6 by Hepatocytes Is a Normal Response to Common Hepatic Stimuli Callie A. Norris 0 Mu He 0 Liang-I Kang 0 Michael Qi Ding 0 Josiah E. Radder 0 Meagan M. Haynes 0 Yu Yang 0 Shirish Paranjpe 0 William C. Bowen 0 Anne Orr 0 George K. Michalopoulos 0 Donna B. Stolz 0 Wendy M. Mars 0 Laurent Renia, Agency for Science, Technology and Research - Singapore Immunology Network, Singapore 0 1 Department of Pathology, University of Pittsburgh, School of Medicine , Pittsburgh , Pennsylvania, United States of America, 2 Department of Cell Biology and Physiology, University of Pittsburgh, School of Medicine , Pittsburgh, Pennsylvania , United States of America 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 NFkB 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. - Funding: This research was supported by National Institutes of Health grants CA103958, CA035373, CA76541, HL094295. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. IL-6 is a key mediator of the acute phase response. Additionally, IL-6 plays a central role in restoring normal hepatic function following liver injury [1,2]. During a general acute phase response, IL-6, produced by immune cells at the site of injury, is deemed to be one of the primary factors that signals liver hepatocytes to produce acute phase proteins [3]. The predominant belief is that IL-6 is released into the circulation, taken up by the liver, and the resident hepatocytes then recognize the IL-6 as a stimulus to begin production of acute phase proteins. Similarly, a principal hypothesis has developed positing that in situations where an injury is inflicted directly upon the liver it is the resident immune cells, such as the Kupffer cells (hepatic macrophages), that primarily produce the IL-6 used for stimulating acute phase protein production. These hepatic immune cells are considered to be the exclusive providers of the IL-6 that subsequently signals hepatocytes in the damaged liver to produce acute phase proteins while helping to restore hepatic function [1,2]. Still, although both IL-6 and these internal immune cells are important for hepatic regeneration [4,5], an exact understanding of how the two contribute to hepatic repair is still wanting. LPS injection is often used to mimic systemic, gram-negative bacterial infections that induce an acute phase response, and IL-6 mRNA production is known to subsequently occur under the transcriptional control of NFkB [6,7]. Maeda et al. established that when NFkB function is selectively inactivated in hepatocytes, IL-6 mRNA production is severely muted in whole livers obtained from mice at 4 h after injection of LPS [6]. As the time frame in which the observed the changes in IL-6 was rapid, and the induced NFkB defect was hepatocyte-specific, these experiments suggested to us that hepatocytes, in addition to immune cells, might also serve as a direct source of IL-6 during an acute phase reaction, i.e. the hepatic response might also have an autocrine component. Previously, it was demonstrated that transplantation of wild type bone marrow into IL-6 deficie (...truncated)


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Callie A. Norris, Mu He, Liang-I Kang, Michael Qi Ding, Josiah E. Radder, Meagan M. Haynes, Yu Yang, Shirish Paranjpe, William C. Bowen, Anne Orr, George K. Michalopoulos, Donna B. Stolz, Wendy M. Mars. Synthesis of IL-6 by Hepatocytes Is a Normal Response to Common Hepatic Stimuli, PLOS ONE, 2014, Volume 9, Issue 4, DOI: 10.1371/journal.pone.0096053