Based on Stat6 gene knockout animal models, the Stat6 signaling pathway has been suggested to play a role in carcinogenesis and Th1/Th2 cytokine balance. Using a semiquantitative EMSA assay and EBV-transformed human B lymphoblast cell lines, we have previously identified three Stat6 activational phenotypes, termed as Stat6high, Stat6low, and Stat6null. A genetic mechanism has been proposed which determines the IL-4-induced activation of the human Stat6 signaling. With respect to the contribution of variant phenotypes to human disease, we further hypothesize that the Stat6null phenotype may result from a partial defect in Stat6 signaling which resembles Stat6 knockout animals in several functional aspects. The characterization of the human Stat6null phenotype stably displayed by the EBV-B cell lines is easily assailable and possesses important implications with respect to Th1/Th2 cytokine imbalance in diseases such as cancer development/metastasis and inflammatory diseases. In this study, we have extended our investigation to the downstream regulatory consequences associated with these Stat6 phenotypes. Production of three important proinflammatory cytokines, IL-12, TNFα and IFNγ was examined in spontaneous EBV-B cell culture using ELISA methodology. Individual cell lines defined as Stat6null produced significantly higher levels of IL-12, TNFα and IFNγ on day 4 in spontaneous culture in comparison with cell lines characterized as Stat6high and Stat6low. These observations of the human Stat6null phenotype, together with those accruing from Stat6 knockout mouse model studies, suggest that the Stat6 signaling pathway may play a role in maintaining the Th1/Th2 cytokine balance by directly and indirectly down-regulating the production of proinflammatory cytokines, a regulatory process which appears to go awry in inflammatory diseases. Moreover, observations from signal transduction studies in our human B lymphocyte model may be compatible with those in the chosen mouse B lymphocyte for establishing signaling networks by the Alliance for Cellular Signaling (AfCS).

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