Interleukin 6 is autoregulated by transcriptional mechanisms in cultures of rat osteoblastic cells.
Interleukin 6 (IL-6), a cytokine produced by skeletal cells, stimulates osteoclast recruitment. The IL-6 soluble receptor (sIL-6R) increases IL-6 activity, and IL-6 and sIL-6R levels are increased in conditions of increased bone resorption. We examined the production of IL-6 by primary rat osteoblasts (Ob cells) cultured in the presence of IL-6 and sIL-6R. IL-6 alone did not induce IL-6 transcripts, but IL-6 was stimulatory in the presence of sIL-6R. Furthermore, sIL-6R by itself increased IL-6 transcripts. Cycloheximide superinduced IL-6 transcripts and did not prevent the effect of IL-6 and sIL-6R. IL-6 in the presence of sIL-6R stimulated IL-6 rates of transcription and the activity of IL-6 promoter fragments in transiently transfected Ob cells. 5' deletions of the IL-6 promoter and targeted mutations of the multiple response element (MRE)/cAMP responsive element (CRE), the nuclear factor for IL-6 (NF-IL-6), and the nuclear factor-kappaB (NF-kappaB) binding sites indicated that NF-IL-6 and NF-kappaB, in combination with MRE/CRE, binding sites are required for the induction of the IL-6 promoter by IL-6. In conclusion, IL-6 induces its own synthesis in osteoblasts by transcriptional mechanisms. This positive feedback may be important in conditions of increased bone resorption.
Franchimont
N
N
Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105, USA.
Rydziel
S
S
Canalis
E
E
D000818:Animals; D001862:Bone Resorption; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D005246:Feedback; D018507:Gene Expression Regulation, Developmental; D015850:Interleukin-6 / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000502:physiology*; D019899:Paracrine Communication; D010294:Parietal Bone / Q000166:cytology / Q000196:embryology; D011401:Promoter Regions, Genetic; D051381:Rats; D019947:Receptors, Interleukin-6 / Q000502:physiology*; D017384:Sequence Deletion; D012995:Solubility; D014158:Transcription, Genetic; D014162:Transfection
D015850:Interleukin-6; D016328:NF-kappa B; D019947:Receptors, Interleukin-6; D003513:Cycloheximide