Disruption by interferon-alpha of an autocrine interleukin-6 growth loop in IL-6-dependent U266 myeloma cells by homologous and heterologous down-regulation of the IL-6 receptor alpha- and beta-chains.
IL-6 is an autocrine growth factor for U266 myeloma cells and their growth is inhibited by IFN-alpha or IL-6 mAb. We asked, therefore, whether IFN-alpha-induced growth inhibition involved IL-6. IFN-alpha and mAb against IL-6, the IL-6R alpha-(gp80) or beta-chain (gp130) potently inhibited U266 cells. Remarkably, this effect occurred despite IFN-alpha-augmented secretion of endogenous IL-6. However, examining the IL-6R revealed that IFN-alpha drastically curtailed expression of the IL-6R alpha- and beta-chain. This effect occurred on two different levels (protein and mRNA) and by two different mechanisms (directly and indirectly through IL-6). First, IFN-alpha, but not IL-6, greatly decreased gp80 and, to a lesser extent, gp130 mRNA levels which resulted in a loss of IL-6 binding sites. Second, IFN-alpha-induced IL-6 predominantly down-regulated membrane-bound gp130. IFN-alpha-mediated decrease of gp80 levels was not detected on IL-6-independent myeloma (RPMI 8226) or myeloid cells (U937). We conclude that IFN-alpha inhibited IL-6-dependent myeloma cell growth by depriving U266 cells of an essential component of their autocrine growth loop, a functional IL-6R.
Schwabe
M
M
Laboratory of Biochemical Physiology, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21701.
Brini
A T
AT
Bosco
M C
MC
Rubboli
F
F
Egawa
M
M
Zhao
J
J
Princler
G L
GL
Kung
H F
HF
D000345:Affinity Labels; D002455:Cell Division / Q000187:drug effects; D003432:Cross-Linking Reagents; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000235:genetics; D019947:Receptors, Interleukin-6; D014407:Tumor Cells, Cultured
D000345:Affinity Labels; D003432:Cross-Linking Reagents; D016207:Cytokines; D016898:Interferon-alpha; D015850:Interleukin-6; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6