Molecular mechanisms regulating induction of interleukin‐6 gene transcription by interferon‐γ

Abstract

The multifunctional cytokine interleukin-6 (IL-6) plays a central role in host defence mechanisms and hematopoiesis. Furthermore, dysregulation of IL-6 gene expression is associated with the pathogenesis of various immunologically related diseases such as myeloma, systemic lupus erythematosus, rheumatoid arthritis, psoriasis and Kaposi's sarcoma. The regulation of IL-6 gene expression occurs mainly at transcriptional level, although mechanisms of post-transcriptional regulation have also been described. In the present study we demonstrate that in HeLa cells, induction of IL-6 by interferon-gamma (IFN-gamma) is transcriptionally controlled, as shown by run on assays and analysis of the IL-6 mRNA stability. Gel-retardation experiments using antibodies specific for factors of the IRF family identified four protein-DNA complexes, which bind to the interferon regulatory factor (IRF) binding site at position -267 to -254, in nuclear extracts from IFN-gamma treated cells. Furthermore, transient transfection analyses of the 5'-flanking region of IL-6 gene linked to the chloramphenicol acetyltransferase (CAT) reporter gene demonstrated that the -267 to -254 IRF site is necessary for IL-6 induction by IFN-gamma. However, transfection experiments in which IRF-1 and I kappa B alpha were overexpressed show that full-scale transcriptional activation of the IL-6 promoter directing CAT expression requires the co-operation between IRF-1 and NF-kappa B at a low constitutive level.

Interleukin-6 ( IL-6 ) and the Prognosis of Abdominal Aortic Aneurysms

“…Furthermore, the overall control of IL-6 expression is extremely complex, partly because of the autocrine effects of IL-6 and its interaction with soluble IL-6 receptors. 16,18,19 Therefore, in subjects with extensive atherosclerosis (most AAA patients), the association between IL-6 genotype and plasma IL-6 may be the converse of that observed in a healthy, younger population. Perhaps surprisingly, we did not detect any association between IL-6 genotype and fibrinogen or CRP.…”

Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice

“…Indeed, mast cells from IL-6 -/-and IFN-γ -/-mice produce negligible IFN-γ and IL-6, suggesting cooperative regulation of these 2 cytokines (19). HeLa cells and monocytes exhibit IFN-γ-regulated expression of IL-6 (38,39). Enhanced IL-6 and IFN-γ, which may come in part from mast cells, were detected in cultured explants of human AAA lesions and in serum of AAA patients (15,40).…”

Activation of src‐family tyrosine kinases by LPS regulates cytokine production in dendritic cells by controlling AP‐1 formation

“…Two members of the IRF family of transcription factors -IRF-1 and ICSBP -are highly induced by LPS, and may play a role in the expression of many cytokines. IL-12 and IL-6 are regulated by one or the other of these factors [22,28], and the promoters of many other cytokines have at least one potential DNA-binding site for one of these regulatory proteins. Indeed, we found that LPS-induced upregulation of both IRF-1 and ICSBP was impaired by inhibition of src-family tyrosine kinases.…”