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 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.
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Callie A
CA
Norris
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Mu
M
He
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Liang-I
LI
Kang
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Michael Qi
MQ
Ding
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Josiah E
JE
Radder
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Meagan M
MM
Haynes
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Yu
Y
Yang
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Shirish
S
Paranjpe
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
William C
WC
Bowen
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Anne
A
Orr
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
George K
GK
Michalopoulos
Department of Cell Biology and Physiology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Donna B
DB
Stolz
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Wendy M
WM
Mars
D000818:Animals; D019898:Autocrine Communication; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D011916:Rats, Inbred F344
D016895:Culture Media, Serum-Free; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor