INTERLEUKIN-6 IS AUTOREGULATED BY TRANSCRIPTIONAL MECHANISMS IN CULTURES OF RAT OSTEOBLASTIC CELLS

Interleukin 6 (IL-6), a cytokine produced by skeletal cells, stimulate s 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 p rimary 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 stim ulatory in the presence of sIL-6R. Furthermore, sIL-6R by itself incre ased 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 o f sIL-6R stimulated IL-6 rates of transcription and the activity of IL -6 promoter fragments in transiently transfected Ob cells. 5' deletion s of the IL-6 promoter and targeted mutations of the multiple response element (MRE)/cAMP responsive element (CRE), the nuclear factor for I L-6 (NF-IL-6), and the nuclear factor-kappa B (NF-kappa B) binding sit es indicated that NF-IL-6 and NF-kappa B, 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.