Transcriptional and post-transcriptional regulation of GM-CSF-induced IL-1β gene expression in PMN

Abstract

Polymorphonuclear leukocytes (PMN) play an important role in inflammation, immune responses, and tissue repair by secreting interleukin- 1 beta (IL-1 beta). We investigated the regulation of IL-1 beta gene expression in human PMN treated with granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF induced IL-1 beta mRNA accumulation at 0.1 ng/ml and maximal induction was observed at 1 ng/ml. IL- 1 beta mRNA levels reached a maximum with 1-2 h after stimulation with GM-CSF and returned to baseline levels by 4-6 h. The time course of IL-1 beta mRNA induction by GM-CSF was more protracted than previously reported for PMN stimulated with tumor necrosis factor-alpha (TNF-alpha, 10 ng/ml). Nuclear run-on analysis indicated that GM-CSF, like TNF, increases IL-1 beta transcription. Kinetic studies with the RNA synthesis inhibitor, actinomycin D, showed that GM-CSF induces stable IL-1B mRNA. Cycloheximide enhanced the IL-1 beta mRNA accumulation by GM-CSF at the level of mRNA stabilization, but blocked IL-1 beta mRNA expression by TNF. Thus, GM-CSF increases IL-1 beta message accumulation in PMN at both the transcriptional and post-transcriptional levels by mechanisms that are different from TNF induction of IL-1 beta gene expression.