Complex of soluble human IL-6-receptor/IL-6 up-regulates expression of acute-phase proteins.
IL-6 is a major regulator of acute phase protein synthesis in the liver. It exerts its action via a plasma membrane receptor consisting of two subunits, a ligand binding 80-kDa glycoprotein and a 130-kDa glycoprotein involved in signal transduction. We genetically generated a soluble form of the 80-kDa subunit of the human IL-6R (shIL-6R) in mouse fibroblasts (NIH/3T3 cells). The shIL-6R added to human hepatoma cells (HepG2) amplified the induction of alpha 1-antichymotrypsin and haptoglobin by IL-6 at the mRNA and protein level. Moreover, a model for a liver permanently exposed to high IL-6 concentrations has been developed; HepG2 cells were stably transfected with human IL-6-cDNA; 10(6) of the transfected cells (HepG2-IL-6) synthesized and secreted 2 micrograms of IL-6 within 24 h. Incubation of these cells with endogenous or exogenous IL-6 did not result in acute-phase protein induction. However, these IL-6-desensitized cells responded to other cytokines such as leukemia inhibitory factor, transforming growth factor beta 1, and IFN-gamma, known to modulate acute phase protein synthesis in the liver. Incubation of HepG2-IL-6 cells with shIL-6R reconstituted their responsiveness to IL-6 in a dose- and time-dependent manner. The possible biologic role that might be played by the shIL-6R in disease is discussed.
Mackiewicz
A
A
Department of Cancer Immunology, Academy of Medicine at Great Poland Cancer Center, Poznan.
Schooltink
H
H
Heinrich
P C
PC
Rose-John
S
S
D000209:Acute-Phase Proteins / Q000378:metabolism*; D015870:Gene Expression; D006242:Haptoglobins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011971:Receptors, Immunologic / Q000737:chemistry / Q000502:physiology*; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins / Q000378:metabolism; D012995:Solubility; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000514:alpha 1-Antichymotrypsin / Q000378:metabolism
D000209:Acute-Phase Proteins; D006242:Haptoglobins; D015850:Interleukin-6; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D000514:alpha 1-Antichymotrypsin