Octamer-binding factor 6 (Oct-6/Pou3f1) is induced by interferon and contributes to dsRNA-mediated transcriptional responses

<p>Abstract</p> <p>Background</p> <p>Octamer-binding factor 6 (Oct-6, Pou3f1, SCIP, Tst-1) is a transcription factor of the Pit-Oct-Unc (POU) family. POU proteins regulate key developmental processes and have been identified from a diverse range of species. Oct-6 expression is described to be confined to the developing brain, Schwann cells, oligodendrocyte precursors, testes, and skin. Its function is primarily characterised in Schwann cells, where it is required for correctly timed transition to the myelinating state. In the present study, we report that Oct-6 is an interferon (IFN)-inducible protein and show for the first time expression in murine fibroblasts and macrophages.</p> <p>Results</p> <p>Oct-6 was induced by type I and type II IFN, but not by interleukin-6. Induction of Oct-6 after IFNβ treatment was mainly dependent on signal transducer and activator of transcription 1 (Stat1) and partially on tyrosine kinase 2 (Tyk2). Chromatin immunopreciptitation experiments revealed binding of Stat1 to the Oct-6 promoter in a region around 500 bp upstream of the transcription start site, a region different from the downstream regulatory element involved in Schwann cell-specific Oct-6 expression. Oct-6 was also induced by dsRNA treatment and during viral infections, in both cases <it>via </it>autocrine/paracrine actions of IFNα/β. Using microarray and RT-qPCR, we furthermore show that Oct-6 is involved in the regulation of transcriptional responses to dsRNA, in particular in the gene regulation of serine/threonine protein kinase 40 (<it>Stk40</it>) and U7 snRNA-associated Sm-like protein Lsm10 (<it>Lsm10)</it>.</p> <p>Conclusion</p> <p>Our data show that Oct-6 expression is not as restricted as previously assumed. Induction of Oct-6 by IFNs and viruses in at least two different cell types, and involvement of Oct-6 in gene regulation after dsRNA treatment, suggest novel functions of Oct-6 in innate immune responses.</p

TYK2 Kinase Activity Is Required for Functional Type I Interferon Responses In Vivo

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in cytokine signalling. In vitro analyses suggest that TYK2 also has kinase-independent, i.e., non-canonical, functions. We have generated gene-targeted mice harbouring a mutation in the ATP-binding pocket of the kinase domain. The Tyk2 kinase-inactive (Tyk2K923E) mice are viable and show no gross abnormalities. We show that kinase-active TYK2 is required for full-fledged type I interferon- (IFN) induced activation of the transcription factors STAT1-4 and for the in vivo antiviral defence against viruses primarily controlled through type I IFN actions. In addition, TYK2 kinase activity was found to be required for the protein’s stability. An inhibitory function was only observed upon over-expression of TYK2K923E in vitro. Tyk2K923E mice represent the first model for studying the kinase-independent function of a JAK in vivo and for assessing the consequences of side effects of JAK inhibitors

Testosterone increases risk-taking for status but not for money

Testosterone has long been thought to increase risk-taking, but evidence supporting this association is mixed. Instead, testosterone’s key role may be to promote status-seeking behaviors. Here, we examined to what extent testosterone administration affects risk preferences for both monetary and social status outcomes, and whether this relationship is moderated by an individuals’ social status. Male participants (N=166) experienced high or low status in a competition task and then played two risk tasks; one involving gambles with only monetary outcomes, and another one involving gambles with non-monetary outcomes that influenced their social rank. We found that testosterone (vs. placebo) altered risk preferences for gains and losses in social rank, but not for monetary gains and losses. Specifically, testosterone increased risk-taking to increase social rank in individuals with high, but not low social status. These results demonstrate a context-dependent role of testosterone in regulating risk-taking for social status

Exogenous testosterone increases status-seeking motivation in men with unstable low social status

Testosterone is associated with status-seeking behaviors such as competition, which may depend on whether one wins or loses status, but also on the stability of one’s status. We examined (1) to what extent testosterone administration affects competition behavior in repeated social contests in men with high or low rank, and (2), whether this relationship is moderated by hierarchy stability, as predicted by the status instability hypothesis. Using a real effort-based design in healthy male participants (N = 173 males), we first found that testosterone (vs. placebo) increased motivation to compete for status, but only in individuals with a low unstable status. A second part of the experiment, tailored to directly compare stable with unstable hierarchies, indicated that exogenous testosterone again increased competitive motivation in individuals with a low unstable status, but decreased competition behavior in men with low stable status. Additionally, exogenous testosterone increased motivation in those with a stable high status. Further analysis suggested that these effects were moderated by individuals’ trait dominance, and genetic differences assessed by the androgen receptor (CAG-repeat) and dopamine transporter (DAT1) polymorphisms. Our study provides evidence that testosterone specifically boosts status-related motivation when there is an opportunity to improve one’s social status. The findings contribute to our understanding of testosterone’s causal role in status-seeking motivation in competition behavior, and indicate that testosterone adaptively increases our drive for high status in a context-dependent manner. We discuss potential neurobiological pathways through which testosterone may attain these effects on behavior

Effects of dopamine D2/3 and opioid receptor antagonism on the trade-off between model-based and model-free behaviour in healthy volunteers

Human behaviour requires flexible arbitration between actions we do out of habit and actions that are directed towards a specific goal. Drugs that target opioid and dopamine receptors are notorious for inducing maladaptive habitual drug consumption; yet, how the opioidergic and dopaminergic neurotransmitter systems contribute to the arbitration between habitual and goal-directed behaviour is poorly understood. By combining pharmacological challenges with a well-established decision-making task and a novel computational model, we show that the administration of the dopamine D2/3 receptor antagonist amisulpride led to an increase in goal-directed or 'model-based' relative to habitual or 'model-free' behaviour, whereas the non-selective opioid receptor antagonist naltrexone had no appreciable effect. The effect of amisulpride on model-based/model-free behaviour did not scale with drug serum levels in the blood. Furthermore, participants with higher amisulpride serum levels showed higher explorative behaviour. These findings highlight the distinct functional contributions of dopamine and opioid receptors to goal-directed and habitual behaviour and support the notion that even small doses of amisulpride promote flexible application of cognitive control.ISSN:2050-084

IFN treatment leads to similar activation of JAKs and STATs in <i>Tyk2^K923E</i> and <i>Tyk2</i>-deficient cells.

<p>BMMΦs were treated with IFNβ (500 U/ml) for 20 min or left untreated. Whole cell extracts were used to determine levels of JAK1 tyrosine phosphorylation and JAK1 expression (left panel) and of TYK2 tyrosine phosphorylation and TYK2 expression (right panel) by immunoprecipitation and Western blot analysis. B.-D. BMMΦs were treated with IFNα (500 U/ml), IFNβ (100 U/ml) or IFNγ (100 U/ml) for 20 min or left untreated. Whole cell extracts were used to determine STAT1α/β tyrosine phosphorylation and levels of STAT1α/β expression (B), levels of STAT2 tyrosine phosphorylation and STAT2 expression (C) and levels of STAT3 tyrosine phosphorylation and STAT3 expression (D) by Western blot analysis. E. BMMΦs were treated with IFNβ (10, 100 or 500 U/ml) for 20 min or left untreated and Western blot analysis performed as described in (B). F. NK cells were treated with the indicated doses of IFNβ for 20 min or left untreated. Levels of tyrosine phosphorylation and protein expression of STAT1α/β and STAT4 were analysed by Western blot. G. NK cells were treated with IFNα (500 U/ml) for the times indicated and STAT1 and 4 analysed as described in (F); H. NK cells were treated with IFNβ (100 U/ml) for the times indicated and STAT1 and 4 analysed as described in (F); ERK p85 (B, C, E-H) and ERK p42 (D) served as a loading control.</p

Transcriptional induction of IFN-responsive genes is similar in <i>Tyk2^K923E</i> and <i>Tyk2^−/−</i> cells.

<p>A.-C. WT, <i>Tyk2^−/−</i> and <i>Tyk2^K923E</i> BMMΦs were treated with IFNα (500 U/ml), IFNβ (100 U/ml) or IFNγ (100 U/ml) for 6 h or left untreated. Total RNA was extracted, reverse-transcribed and analysed by RT-qPCR for expression of <i>Oas1a</i>, <i>Ifit1</i> (A), <i>Cxcl1</i>, <i>Socs1</i> (B) and <i>Irf7, Tap1</i> (C). <i>Ube2D2</i> was used for normalization and expression levels were calculated relative to untreated WT cells. Data are derived from three independent experiments and depicted as mean values (+/− SE). D. WT, <i>Tyk2^−/−</i> and <i>Tyk2^K923E</i> BMMΦs were treated with indicated doses of IFNβ for 6 h. Target gene expression was determined as described in A-C. Mean values (+/− SD) derived from two independent experiments are depicted. Note that due to sample size a statistical analysis was not performed.</p