INTERLEUKIN-6 WITH ITS SOLUBLE RECEPTOR ENHANCES THE EXPRESSION OF INSULIN-LIKE GROWTH-FACTOR-I IN OSTEOBLASTS

Interleukin (IL)-6, a cytokine produced by skeletal cells and known to increase bone resorption, has mitogenic effects for bone cells, pos s ibly by regulating the synthesis of other local factors. We tested the effects of IL-6 and its soluble receptor (IL-6sR) on the expression o f insulin-like growth factor (IGF)-I and IGF-II in cultured osteoblast -enriched cells from fetal rat calvariae (Ob cells). IL-6 did not modi fy IGF-I messenger RNA (mRNA) levels, but when tested in the presence of IL-6sR, IL-6 at 1 to 100 ng/ml increased IGF-I transcripts by up to 3.2-fold after 24 h. IL-6sR caused a small increase in IGF-I mRNA lev els when tested alone. IL-6 and IL-6sR increased immunoreactive IGF-I levels by 2.4-fold after 24 h and 6.4-fold after 48 h. Cycloheximide p revented, and indomethacin markedly decreased, the effect of IL-6 and IL-6sR on IGF-I mRNA levels, but hydroxyurea did not. IL-6 and IL-6sR did not alter the decay of IGF-I mRNA in transcriptionally arrested Ob cells, and the half-life of the predominant 6.5-kb IGF-I transcript w as about 11 h in control and treated cells. In addition, IL-6 and IL-6 sR increased the levels of IGF-I heterogeneous nuclear RNA. IL-11 also increased IGF-I mRNA levels, whereas oncostatin M and leukemia-inhibi tory factor did not. In contrast to their effects on IGF-I, IL-6 and I L-6sR caused only a modest increase in IGF-II mRNA and polypeptide lev els. In conclusion, IL-6, in the presence of IL-6sR, increases IGF-I s ynthesis in Ob cells; this effect may lead to a secondary increase in bone formation.