Massive liver growth in mice induced by systemic interleukin 6 administration

Teresa Zimmers, Iain H. McKillop, Robert H. Pierce, Joo Yeon Yoo, Leonidas Koniaris

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

The multifunctional cytokine interleukin 6 (IL-6) is expressed in a wide variety of disease states and pathologic processes. Mice deficient in IL-6 display abnormal and delayed liver regeneration and repair. Currently, IL-6 is thought to influence liver growth indirectly by priming hepatocytes to respond to growth factors such as hepatocyte growth factor (HGF) by inducing expression of HGF and by inhibiting hepatocyte apoptosis, as distinct from the direct mitotic effects of IL-6 on myeloid and other cell types. Here, we show that systemic administration of IL-6 using CHO cell tumors in nude mice results in dramatic hepatomegaly and hepatocyte hyperplasia in the absence of liver injury. Liver mass and liver to body mass ratios increased to 2 to 3 times normal because of proliferation of hepatocytes. Liver growth was associated with high levels of serum IL-6 and with activation of the IL-6-signaling pathway, including increased expression of IL-6 receptor-α/gp80, activation of the signal transducer and activator of transcription-3 (STAT-3), and mitogen-activated protein kinase (MAPK/ERK)-signaling pathways and induction of downstream target genes, including c-myc. HGF receptor and transforming growth factor α (TGF-α)/epidermal growth factor (EGF) receptor activation were decreased in hypertrophied livers, suggesting that IL-6-induced liver growth was independent of these known hepatocyte mitotic pathways. In conclusion, we suggest that IL-6 may function as a direct hepatic mitogen in vivo and, furthermore, that IL-6 warrants closer examination as a potent liver growth factor with potential clinical utility for increasing liver mass following injury.

Original languageEnglish (US)
Pages (from-to)326-334
Number of pages9
JournalHepatology
Volume38
Issue number2
DOIs
StatePublished - Aug 1 2003
Externally publishedYes

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Interleukin-6
Liver
Growth
Hepatocytes
Hepatocyte Growth Factor
Proto-Oncogene Proteins c-met
Interleukin-6 Receptors
STAT3 Transcription Factor
myc Genes
Liver Regeneration
Hepatomegaly
CHO Cells
MAP Kinase Signaling System
Wounds and Injuries
Transforming Growth Factors
Myeloid Cells
Pathologic Processes
Mitogen-Activated Protein Kinases
Mitogens
Epidermal Growth Factor Receptor

ASJC Scopus subject areas

  • Hepatology

Cite this

Massive liver growth in mice induced by systemic interleukin 6 administration. / Zimmers, Teresa; McKillop, Iain H.; Pierce, Robert H.; Yoo, Joo Yeon; Koniaris, Leonidas.

In: Hepatology, Vol. 38, No. 2, 01.08.2003, p. 326-334.

Research output: Contribution to journalArticle

Zimmers, Teresa ; McKillop, Iain H. ; Pierce, Robert H. ; Yoo, Joo Yeon ; Koniaris, Leonidas. / Massive liver growth in mice induced by systemic interleukin 6 administration. In: Hepatology. 2003 ; Vol. 38, No. 2. pp. 326-334.
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