Synthesis of IL-6 by hepatocytes is a normal response to common hepatic stimuli

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 inj...

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Bibliographic Details
Published in:PloS one 2014-04, Vol.9 (4), p.e96053
Main Authors: Norris, Callie A, He, Mu, Kang, Liang-I, Ding, Michael Qi, Radder, Josiah E, Haynes, Meagan M, Yang, Yu, Paranjpe, Shirish, Bowen, William C, Orr, Anne, Michalopoulos, George K, Stolz, Donna B, Mars, Wendy M
Format: Article
Language:English
Subjects:
Acute phase proteins
Acute phase substances
Analysis
Animal models
Animals
Autocrine Communication
Autocrine signalling
Bacteria
Biological models (mathematics)
Biology and Life Sciences
Care and treatment
Cells, Cultured
Culture Media, Serum-Free
Cytokines
Diagnosis
Growth factors
Health aspects
Hepatectomy
Hepatocyte Growth Factor - metabolism
Hepatocyte Growth Factor - pharmacology
Hepatocytes
Hepatocytes - drug effects
Hepatocytes - metabolism
Hepatology
Hepatotoxicity
Homeostasis
Hypotheses
Immune system
Interleukin
Interleukin 6
Interleukin 6 receptors
Interleukin-6 - biosynthesis
Interleukin-6 - genetics
Interleukin-6 - metabolism
Interleukins
Kinases
Lipopolysaccharides
Lipopolysaccharides - pharmacology
Liver
Liver - drug effects
Liver - immunology
Liver - metabolism
Liver cells
Liver diseases
Macrophages - metabolism
Medicine
Medicine and Health Sciences
Mice, Inbred C57BL
NF-κB protein
Paracrine signalling
Pathology
Physiology
Proteins
Rats, Inbred F344
Research and Analysis Methods
Risk factors
RNA, Messenger - metabolism
Rodents
Synthesis
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0096053