Coexpression of IL-6 and soluble IL-6R causes nodular regenerative hyperplasia and adenomas of the liver.
Studies with tumor necrosis factor p55 receptor- and interleukin-6 (IL-6)-deficient mice have shown that IL-6 is required for hepatocyte proliferation and reconstitution of the liver mass after partial hepatectomy. The biological activities of IL-6 are potentiated when this cytokine binds soluble forms of its specific receptor subunit (sIL-6R) and the resulting complex interacts with the transmembrane signaling chain gp130. We show here that double transgenic mice expressing high levels of both human IL-6 and sIL-6R under the control of liver-specific promoters spontaneously develop nodules of hepatocellular hyperplasia around periportal spaces and present signs of sustained hepatocyte proliferation. The resulting picture is identical to that of human nodular regenerative hyperplasia, a condition frequently associated with immunological and myeloproliferative disorders. In high expressors, hyperplastic lesions progress with time into discrete liver adenomas. These data strongly suggest that the IL-6/sIL-6R complex is both a primary stimulus to hepatocyte proliferation and a pathogenic factor of hepatocellular transformation.
Istituto Ricerche di Biologia Molecolare (IRBM) P.Angeletti, Via Pontina Km 30.600, 00400 Pomezia, Rome.
D
D
Maione
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E
Di Carlo
W
W
Li
P
P
Musiani
A
A
Modesti
M
M
Peters
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S
Rose-John
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C
Della Rocca
M
M
Tripodi
D
D
Lazzaro
R
R
Taub
R
R
Savino
G
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Ciliberto
D000236:Adenoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004730:Endothelium, Vascular; D005786:Gene Expression Regulation; D006242:Haptoglobins / Q000096:biosynthesis; D006965:Hyperplasia / Q000401:mortality; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008115:Liver Regeneration; D051379:Mice; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D019947:Receptors, Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D050796:STAT3 Transcription Factor; D012995:Solubility; D015534:Trans-Activators / Q000096:biosynthesis
D004268:DNA-Binding Proteins; D006242:Haptoglobins; D015850:Interleukin-6; D016271:Proto-Oncogene Proteins c-myc; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators