ENDOTHELIN STIMULATES OSTEOBLASTIC PRODUCTION OF IL-6 BUT NOT MACROPHAGE-COLONY-STIMULATING FACTOR

Endothelins (ET) are vasoactive polypeptide hormones that stimulate os teoblastic signal transduction events. Using MC3T3-E1 and primary oste oblasts, we studied ET effects on interleukin-6 (IL-6) and macrophage colony-stimulating factor (M-CSF) production. Enzyme-linked immunosorb ent assay analysis showed a dose-dependent 3- to 3.5-fold increase in IL-6 with 100 nM ET-1 stimulation within 4 (primary osteoblasts) to 8 (MC3T3-E1) h. ET-3 was less effective at enhancing IL-6 production, wi th a maximal twofold increase after 100 nM ET-3 after 4 h. No signific ant increase in M-CSF production was noted with ET-1 or ET-3 in either cell type. Reverse-transcriptase polymerase chain reaction analysis d emonstrated both ET(A) and ET(B) receptors on primary osteoblasts and only ET(A) receptors on MC3T3-E1. ET-l-stimulated IL-6 production was blocked by the inhibitor BQ-123, implicating ET(A) receptor involvemen t. Increased IL-6 protein was coupled with elevated IL-6 mRNA levels a nd a twofold increase in IL-6 message half-life.