Signal transducer and activator of transcription (STAT) proteins are critical mediators of cytokine signaling. Among the seven STAT proteins, STAT6 is activated by IL-4 and IL-13 and plays a predominant role in the immune system. However, there is increasing evidence that STAT6 may function in other tissues and organ systems. IL-4, IL-13, and STAT6 promote humoral immunity, clearance of helminthic parasites as well as the pathogenesis of allergic disorders like asthma, food allergies, and atopic dermatitis. In this review, we will describe our current understanding of the biological functions of STAT6 and summarize recent advances in understanding the molecular mechanisms by which STAT6 regulates transcription.

T helper cell effector subsets develop in response to specific cytokine environments. The development of a particular cytokine-secreting pattern requires an integration of signals that may promote the development of opposing pathways. A recent example of this paradigm is the IL-9-secreting Th9 cell that develops in response to TGFβ and IL-4, cytokines that in isolation promote the development of iTregs and Th2 cells, respectively. To determine how the balance of these factors results in priming for IL-9 secretion, we examined the effects of each pathway on transcription factors that regulate T helper cell differentiation. We demonstrate that TGFβ induces the PU.1-encoding Sfpi1 locus and that this is independent of IL-4-induced STAT6 activation. IL-4-activated STAT6 is required for repressing the expression of T-bet and Foxp3 in Th9 cells, transcription factors that inhibit IL-9 production, and is required for the induction of IRF4, which promotes Th9 development. These data establish a transcription factor network that regulates IL-9, and demonstrates how combinationsof cytokine signals generate cytokine-secreting potential by altering the expression of a panel of transcription factors.

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Background Interleukin-4 (IL-4) and STAT6 play an important role in progression of allergic airway disease (AAD) or asthma. IL-4 and STAT6 mediate T helper 2 (Th2) responses in T cells, and immunoglobulin class switching to IgE in B cells. Both, Th2 responses and IgE promote the asthmatic condition. We have previously demonstrated that PARP-14, a member of the poly ADP-ribose polymerase (PARP) family of proteins regulates the transcription function of STAT6. However, the role of PARP-14 in AAD is not known. Objective Here we investigate the role of PARP-14 and the enzyme activity associated with it in AAD dependent on airway hyper-responsiveness (AHR) and lung inflammation. We also elucidate the mechanism by which PARP-14 regulates AAD. Methods The role of PARP-14 and its enzyme activity in AAD and Th2 differentiation were examined using a mouse model of AAD and in vitro T helper cell differentiation. Results PARP-14 deficient animals when compared to controls show reduced lung pathology and IgE. Treating mice with a pharmacological inhibitor for PARP activity reduced the severity of AHR and lung inflammation. Mechanistically, our data indicate that PARP-14 and its enzyme activity aid in the differentiation of T cells towards a Th2 phenotype by regulating the binding of STAT6 to the Gata3 promoter. Conclusion PARP-14 and the catalytic activity associated with it promote Th2 differentiation and AAD in a murine model, and targeting PARP-14 may be a potential new therapy for allergic asthma.

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Inducible protection from apoptosis in vivo controls the size of cell populations. An important question in this respect is how differentiation affects mechanisms of apoptosis regulation. Among mature T lymphocytes, the NF-jB/Rel transcription factors are coupled to receptors that control cell population sizes by concurrently regulating survival and multiplication. In the present study, we used a transgenic inhibitor of NF-jB/Rel signaling to investigate the role of this pathway in proliferation and death of mature T cells in vivo.The results indicate that NF-jB integrates two critical yet distinct molecular pathways preventing apoptosis affected by the death receptor Fas, coordinately regulating levels of FLIP and Bcl-x L in primary T cells. Surprisingly, NF-jB blockade preferentially impacted naive as compared to memory T cells. The Fas/FasL pathway was linked to these findings by evidence that the abnormalities imposed by NF-jB inhibition were ameliorated by Fas deficiency, particularly for the CD4 + lineage. Moreover, levels of an inhibitor of Fas-mediated apoptosis, c-FLIP, were diminished in cells expressing the transgenic inhibitor. NF-jB was also linked to T cell survival in vivo by mediating induction of Bcl-x L : restoration of Bcl-x L levels reversed the preferential deficit of naive T cells, differentially impacting the CD4 and CD8 subsets. These results show that promoting survival and effective multiplication are central roles for NF-jB in T lymphoid homeostasis in vivo, but this effect and its underlying mechanisms are influenced by the developmental state of the lymphocyte.