Tumor necrosis factor-alpha and IL-6 up-regulate IFN-gamma receptor gene expression in human monocytic THP-1 cells by transcriptional and post-transcriptional mechanisms.
IFN-gamma is a potent activator of monocytic cell functions, including the stimulation of TNF-alpha and the control of IL-6 synthesis. These cytokines might act as autocrine or paracrine factors together with IFN-gamma in inducing biologic responses. In this study, we addressed the question of whether or not TNF-alpha and IL-6 play a role in modulating of IFN-gamma binding. Expression of IFN-gamma surface receptor was measured in the human monocytic THP-1 cells. The capacity of these cells to bind IFN-gamma increased with time after treatment with each cytokine. The number of IFN-gamma R per cell rose by three- and fourfold after 16 h of treatment with TNF-alpha and IL-6, respectively. Scatchard analysis of binding data showed that neither TNF-alpha nor IL-6 affected the affinity of IFN-gamma for its receptor. The increased surface expression of IFN-gamma R induced by TNF-alpha and IL-6 correlated with the rise in IFN-gamma mRNA receptor levels. TNF-alpha-mediated up-regulation of IFN-gamma R was due to an increase in transcriptional activity of the IFN-gamma R gene, as shown by run-on experiments. No significant modulation of IFN-gamma R gene transcription was observed in nuclei from cells treated with IL-6, whose effect appeared to be related to IFN-gamma mRNA receptor stabilization. Taken together, the present results provide, to our knowledge, the first evidence for cytokine-mediated up-regulation of IFN-gamma R in human monocytic cells. This up-regulation by TNF-alpha and IL-6, which are both produced by monocytes, occurs through different mechanisms, and may be of physiologic relevance in host defense.
Sanceau
J
J
Unité 196 INSERM Interférons et Cytokines, Institut Curie, Paris, France.
Merlin
G
G
Wietzerbin
J
J
D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D015850:Interleukin-6 / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D011971:Receptors, Immunologic / Q000032:analysis / Q000235:genetics*; D017471:Receptors, Interferon; D014158:Transcription, Genetic / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation
D015850:Interleukin-6; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma