The phosphatidylinositol 3-kinase/Akt pathway plays an important role in the signaling of insulin and other growth factors, which reportedly attenuate the interleukin-6 (IL-6)-mediated stimulation of acute phase plasma protein genes. We investigated the effect of the protein kinase Akt on IL-6-mediated transcriptional activation. The transient expression of constitutively active Akt inhibited the IL-6-dependent activity of the alpha(2)-macroglobulin promoter in HepG2 cells, whereas expression of an inactive mutant of phosphatidylinositol-dependent kinase 1 had the opposite effect. Since Akt is known to regulate gene expression through inactivation of the transcription factor FKHR (forkhead in rhabdomyosarcoma), we examined the effect of FKHR on STAT3-mediated transcriptional regulation. Indeed, the overexpression of FKHR specifically enhanced the activity of STAT3-dependent promoters but not that of a STAT5-responsive promoter. The effect of FKHR required the presence of functional STAT3 and was abrogated by the expression of dominant negative STAT3 mutants. Furthermore, FKHR and STAT3 were shown to coimmunoprecipitate and to colocalize in the nuclear regions of IL-6-treated HepG2 cells. Our results indicate that FKHR can modulate the IL-6-induced transcriptional activity by acting as a coactivator of STAT3.

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Insulin has been described to attenuate the interleukin-6 (IL-6)mediated stimulation of acute phase plasma protein genes. Since insulin stimulation results in activation of the PI 3-kinase/Akt pathway, we tested the effect of Akt on the STAT3-dependent transcription of alpha2-macroglobulin (a2-m). We found in transicntly transfected HepG2 cells that expression of catalytically inactive PDKl increased the IL-6-induced a2-m reporter gene activity about 1.5 -fold. Co-transfection of constitutively active Akt inhibited the IL-6-induced a2m-expression by about 40%. Since Akt is known to regulate gene expression through inactivation of the transcription factor FKHR, we speculated that FKHR might be involved in the STAT3 dependent expression of a2-m. We found that co-expression of FKHR increased the IL-6induced a2-m reporter gene activity about three -fold. Co-immunoprecipitation experiments showed a direct interaction between STAT3 and FKHR.Modulation of STAT3 Gene Transcription through the PI 3-Kinase/Akt Pathway: Interaction between the Transcription

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