Hypoxia signaling pathway: A central mediator in endocrine tumors.

Adequate oxygen levels are essential for the functioning and maintenance of biological processes in virtually every cell, albeit based on specific need. Thus, any change in oxygen pressure leads to modulated activation of the hypoxia pathway, which affects numerous physiological and pathological processes, including hematopoiesis, inflammation, and tumor development. The Hypoxia Inducible Factors (HIFs) are essential transcription factors and the driving force of the hypoxia pathway; whereas, their inhibitors, HIF prolyl hydroxylase domain (PHDs) proteins are the true oxygen sensors that critically regulate this response. Recently, we and others have described the central role of the PHD/HIF axis in various compartments of the adrenal gland and its potential influence in associated tumors, including pheochromocytomas and paragangliomas. Here, we provide an overview of the most recent findings on the hypoxia signaling pathway in vivo, including its role in the endocrine system, especially in adrenal tumors.

Transient Depletion of Foxp3+ Regulatory T Cells Selectively Promotes Aggressive ß Cell Autoimmunity in Genetically Susceptible DEREG Mice.

Type 1 diabetes (T1D) represents a hallmark of the fatal multiorgan autoimmune syndrome affecting humans with abrogated Foxp3+ regulatory T (Treg) cell function due to Foxp3 gene mutations, but whether the loss of Foxp3+ Treg cell activity is indeed sufficient to promote ß cell autoimmunity requires further scrutiny. As opposed to human Treg cell deficiency, ß cell autoimmunity has not been observed in non-autoimmune-prone mice with constitutive Foxp3 deficiency or after diphtheria toxin receptor (DTR)-mediated ablation of Foxp3+ Treg cells. In the spontaneous nonobese diabetic (NOD) mouse model of T1D, constitutive Foxp3 deficiency did not result in invasive insulitis and hyperglycemia, and previous studies on Foxp3+ Treg cell ablation focused on Foxp3DTR NOD mice, in which expression of a transgenic BDC2.5 T cell receptor (TCR) restricted the CD4+ TCR repertoire to a single diabetogenic specificity. Here we revisited the effect of acute Foxp3+ Treg cell ablation on ß cell autoimmunity in NOD mice in the context of a polyclonal TCR repertoire. For this, we took advantage of the well-established DTR/GFP transgene of DEREG mice, which allows for specific ablation of Foxp3+ Treg cells without promoting catastrophic autoimmune diseases. We show that the transient loss of Foxp3+ Treg cells in prediabetic NOD.DEREG mice is sufficient to precipitate severe insulitis and persistent hyperglycemia within 5 days after DT administration. Importantly, DT-treated NOD.DEREG mice preserved many clinical features of spontaneous diabetes progression in the NOD model, including a prominent role of diabetogenic CD8+ T cells in terminal ß cell destruction. Despite the severity of destructive ß cell autoimmunity, anti-CD3 mAb therapy of DT-treated mice interfered with the progression to overt diabetes, indicating that the novel NOD.DEREG model can be exploited for preclinical studies on T1D under experimental conditions of synchronized, advanced ß cell autoimmunity. Overall, our studies highlight the continuous requirement of Foxp3+ Treg cell activity for the control of genetically pre-installed autoimmune diabetes.