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.
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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)