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Cross-talk between interferon-? and hedgehog signaling regulates adipogenesis.

ABSTRACT: OBJECTIVE: T cells and level of the cytokine interferon-? (IFN-?) are increased in adipose tissue in obesity. Hedgehog (Hh) signaling has been shown to potently inhibit white adipocyte differentiation. In light of recent findings in neurons that IFN-? and Hh signaling cross-talk, we examined their potential interaction in the context of adipogenesis. RESEARCH DESIGN AND METHODS: We used Hh reporter cells, cell lines, and primary adipocyte differentiation models to explore costimulation of IFN-? and Hh signaling. Genetic dissection using Ifngr1(-/-) and Stat1(-/-) mouse embryonic fibroblasts, and ultimately, anti-IFN-? neutralization and expression profiling in obese mice and humans, respectively, were used to place the findings into the in vivo context. RESULTS: T-cell supernatants directly inhibited hedgehog signaling in reporter and 3T3-L1 cells. Intriguingly, using blocking antibodies, Ifngr1(-/-) and Stat1(-/-) cells, and simultaneous activation of Hh and IFN-? signaling, we showed that IFN-? directly suppresses Hh stimulation, thus rescuing adipogenesis. We confirmed our findings using primary mouse and primary human (pre)adipocytes. Importantly, robust opposing signals for Hh and T-cell pathways in obese human adipose expression profiles and IFN-? depletion in mice identify the system as intact in adipose tissue in vivo. CONCLUSIONS: These results identify a novel antagonistic cross-talk between IFN-? and Hh signaling in white adipose tissue and demonstrate IFN-? as a potent inhibitor of Hh signaling.

SUBMITTER: Todoric J

PROVIDER: S-EPMC3114396 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Cross-talk between interferon-γ and hedgehog signaling regulates adipogenesis.

Todoric Jelena J Strobl Birgit B Jais Alexander A Boucheron Nicole N Bayer Martina M Amann Sabine S Lindroos Josefine J Teperino Raffaele R Prager Gerhard G Bilban Martin M Ellmeier Wilfried W Krempler Franz F Müller Mathias M Wagner Oswald O Patsch Wolfgang W Pospisilik J Andrew JA Esterbauer Harald H

Diabetes 20110502 6

<h4>Objective</h4>T cells and level of the cytokine interferon-γ (IFN-γ) are increased in adipose tissue in obesity. Hedgehog (Hh) signaling has been shown to potently inhibit white adipocyte differentiation. In light of recent findings in neurons that IFN-γ and Hh signaling cross-talk, we examined their potential interaction in the context of adipogenesis.<h4>Research design and methods</h4>We used Hh reporter cells, cell lines, and primary adipocyte differentiation models to explore costimulat ...[more]

PMID: 21536945

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Project description:Despite effective antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) are found in nearly one-third of patients. Using a cellular co-culture system including neurons and human microglia infected with HIV (hμglia/HIV), we investigated the hypothesis that HIV-dependent neurological degeneration results from the periodic emergence of HIV from latency within microglial cells in response to neuronal damage or inflammatory signals. When a clonal hμglia/HIV population (HC69) expressing HIV, or HIV infected human primary and iPSC-derived microglial cells, were cultured for a short-term (24 h) with healthy neurons, HIV was silenced. The neuron-dependent induction of latency in HC69 cells was recapitulated using induced pluripotent stem cell (iPSC)-derived GABAergic cortical (iCort) and dopaminergic (iDopaNer), but not motor (iMotorNer), neurons. By contrast, damaged neurons induce HIV expression in latently infected microglial cells. After 48-72 h co-culture, low levels of HIV expression appear to damage neurons, which further enhances HIV expression. There was a marked reduction in intact dendrites staining for microtubule associated protein 2 (MAP2) in the neurons exposed to HIV-expressing microglial cells, indicating extensive dendritic pruning. To model neurotoxicity induced by methamphetamine (METH), we treated cells with nM levels of METH and suboptimal levels of poly (I:C), a TLR3 agonist that mimics the effects of the circulating bacterial rRNA found in HIV infected patients. This combination of agents potently induced HIV expression, with the METH effect mediated by the σ1 receptor (σ1R). In co-cultures of HC69 cells with iCort neurons, the combination of METH and poly(I:C) induced HIV expression and dendritic damage beyond levels seen using either agent alone, Thus, our results demonstrate that the cross-talk between healthy neurons and microglia modulates HIV expression, while HIV expression impairs this intrinsic molecular mechanism resulting in the excessive and uncontrolled stimulation of microglia-mediated neurotoxicity.

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Cross-talk between interferon-? and hedgehog signaling regulates adipogenesis.

Publications

Cross-talk between interferon-γ and hedgehog signaling regulates adipogenesis.

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