Differential role of tyrosine phosphorylation in adhesion-induced transcription, mRNA stability, and cytoskeletal organization in human monocytes

Monocyte adhesion resulted hi rapid tyrosine phosphorylation and subsequent cytokine mRNA induction. The objective of this study was to determine the role of specific tyrosine phosphorylation events, particularly those involv ing members of the MAP kinase family, in regulating adhesion-induced cytoki ne expression. Using nuclear run-on analyses, we demonstrated that on adhes ion, monocytes rapidly transcriptionally activated numerous cytokine mRNAs, coincident with the activation of the transcription factors NF-kappa B and AP-1. Both an inhibitor of tyrosine phosphorylation, genistein, and the cy toplasmic tyrosine phospatase PTP1B, were unable to prevent adhesion-mediat ed transcriptional activation. However, both blocked adhesion-induced ERK a nd JNK but not p38 kinase activation and at the same time decreased the sta bility of interleukin-1 beta (IL-1 beta) and IL-8 transcripts. In addition, ,whereas adhesive events occurred in the presence of genistein and PTP1B, m onocyte spreading was markedly inhibited. Our results suggest that the majo rity of protein phosphorylation events are associated with adhesion-induced cytokine expression through transcript stabilization and cytoskeletal orga nization. A minority of protein phosphorylation events, not sensitive to ge nistein or PTP1B exposure, may be instrumental in regulating transcription. Thus the spectrum of protein tyrosine kinases required for transcription a ppear distinct from those involved in maintaining the stability of some cyt okine mRNAs and the integrity of the cytoskeleton to which mRNA destined fo r translation must be associated.