Signal Transducer and Activation of Transcription (STAT) 4β, a Shorter Isoform of Interleukin-12-Induced STAT4, Is Preferentially Activated by Estrogen

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Abstract
Estrogen, a natural immunomodulatory compound, has been shown to promote the induction of a prototype T helper 1 cytokine, interferon (IFN)-γ, as well as to up-regulate IFNγ-mediated proinflammatory molecules (nitric oxide, cyclooxygenase 2, monocyte chemoattractant protein 1). Because IL-12 is a major IFNγ-inducing cytokine, in this study we investigated whether estrogen treatment of wild-type C57BL/6 mice alters IL-12-mediated signaling pathways. A recent study has shown that IL-12 activates two isoforms of signal transducer and activation of transcription (STAT) 4, a normal-sized (full-length STAT4α) and a truncated form (STAT4β). Interestingly, we found that estrogen treatment preferentially up-regulates the phosphorylation of STAT4β in splenic lymphoid cells. Time kinetic data showed the differential activation of STAT4β in splenic lymphoid cells from estrogen-treated mice, but not in cells from placebo controls. The activation of STAT4β was mediated by IL-12 and not IFNγ because deliberate addition or neutralization of IL-12, but not IFNγ, affected the activation of STAT4β. In contrast to IL-12-induced activation of STAT4β in cells from estrogen-treated mice, STAT4α was not increased, rather it tended to be decreased. In this context, STAT4α-induced p27kip1 protein was decreased in concanavalin A + IL-12-activated lymphocytes from estrogen-treated mice only. By using the in vitro DNA binding assay, we confirmed the ability of pSTAT4β to bind to the IFNγ-activated sites (IFNγ activation sequences)/STAT4-binding sites in estrogen-treated mice. Our data are the first to show that estrogen apparently has selective effects on IL-12-mediated signaling by preferentially activating STAT4β. These novel findings are likely to provide new knowledge with regard to estrogen regulation of inflammation. IL-12 activates cells through STAT4 signaling. Two isoforms of STAT4 have now been identified: a normal-sized STAT4α and a shorter STAT4β. Estrogens preferentially activate STAT4β isoform.