Stimulation of human peripheral blood granulocytes with the proinflammatory cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), increases incorporation of [ 3 H]uridine into RNA. We investigated the nature of the RNA synthesized under these conditions. Using transcription inhibitors, gel electrophoresis, and high-salt precipitation, it was concluded that as much as 90% of this radiolabeled RNA represents polymerase II transcripts. Differential display reverse transcription-polymerase chain reaction was used to identify and clone GM-CSF-responsive mRNAs. Serum-and glucocorticoid-regulated kinase (sgk) mRNA was identified that could be up-regulated 10-to 20-fold by Ն0.1 ng/mL recombinant human GM-CSF. The 2.6-kb sgk mRNA was induced rapidly (within 30 min) by GM-CSF and remained at high levels for at least 12 h. Up-regulation was blocked completely by the transcription inhibitor, actinomycin D, but not by the translation inhibitor, cycloheximide, nor by the tyrosine kinase inhibitor, genistein. Up-regulation did not appear to be caused by enhanced mRNA stability. Other inflammatory mediators could also increase sgk mRNA levels (GM-CSF GG lipopolysaccharide G fMLP ؍ tumor necrosis factor ␣). The function of sgk in granulocytes remains unknown. J. Leukoc. Biol. 67: 240-248; 2000.