Regulation of Cytokine and Growth Factor Gene Expression in Human Bone Marrow Stromal Cells Transformed With Simian Virus

Marrow stromal cells are thought t o regulate hematopoiesis by producing colony-stimulating factors (CSFs) and other cytokines, either constitutively or in response to mediators such as interleukin-la (IL-la) or tumor necrosis factor-a (TNFa). The mechanisms by which these inflammatory cytokines induce CSF expression in stromal cells are not fully defined. In this study, we used human marrow stromal cells transformed by simian virus 40 (SV-MSCs) to study growth factor and cytokine gene regulation in response t o ILla and TNFa. ILla induced significant and prolonged increases in steady-state mRNA levels for interleukin-6 (IL-6). interleukin-1s (IL-lfi), granulocyte-macrophage CSF (GM-CSF). and, t o a lesser extent, granulocyteCSF (G-CSF); this induction was not dependent on new protein synthesis. Nuclear run-on analyses showed that ILla transcriptionally activated the genes for IL-6, GMCSF, and IL-18. while TNFa transcriptionally induced expression of IL-6 and IL-1s. Furthermore, mRNA for IL-6 and