Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and Cyclin D1

Abstract

Regulation of apoptosis and cell cycle progression plays an essential role in the maintenance of B-cell homeostasis, because a fine balance of survival and expansion is critical for preventing lymphocytic disorders. Although remarkable progress in understanding B-cell development has been achieved, much less is known concerning niches that are critical to the maintenance of B-cell homeostasis. Leptin has recently been recognized to be important for modulating the immune responses, but it has remained unclear how leptin signaling influences B-cell physiology. A variety of lymphocytic malignancies have been reported to be linked to leptin, and therefore it is necessary to elucidate the mechanisms involved. Here we demonstrate that leptin promotes B-cell homeostasis by inhibiting apoptosis and by inducing cell cycle entry through the activation of expressions of B-cell CLL/lymphoma 2 (Bcl-2) and cyclin D1. We further show that leptin can induce Bcl-2 and cyclin D1 expression by two pathways, including the direct activation of their promoters and suppression of microRNAs (miRNAs) that target their putative 3′untranslated regions. Amplification of these leptin-modulated miRNAs inhibited B lymphoma cell growth. These findings provide insights into mechanisms for leptin regulation of the humoral immune system and suggest new therapeutic strategies for leptin receptor expressing malignancies.B cell survival | apoptosis | proliferation | microRNA A poptosis plays an essential role in the maintenance of B-cell homeostasis, a process that is regulated by a fine balance between the continual generation of new B lymphocytes and their elimination through multiple checkpoints in both bone marrow (BM) and secondary lymphoid organs (1). The balance between B cell survival and death is critical because excessive apoptosis may lead to immunodeficiencies whereas insufficient apoptosis may result in autoimmunity and even lymphoid malignancies (2). B cells that are optimally activated escape apoptosis and transit through different cell cycle checkpoints. B-cell CLL/lymphoma 2 (Bcl-2) family proteins, which function to preserve or disturb mitochondrial integrity, are required for the maintenance of immune homeostasis (2, 3). Targeted loss of the antiapoptotic member gene Bcl-2 has led to massive apoptosis of lymphocytes, whereas overexpression of Bcl-2 has caused the accumulation of B cells (4, 5). D-type cyclins are key players in the G 1 checkpoint control mechanism and are critical for cell proliferation (6). Both Bcl-2 and D-type cyclins are prime targets for novel therapeutics because their overexpression is common in many hematological diseases and many types of cancers (7,8). MicroRNAs (miRNAs) are increasingly recognized for their prominent role in immune homeostasis, while the accumulating evidence for aberrant miRNA expression in B-cell-derived tumors underscores miRNAs as potential targets for cancer therapeutics (9). Therefore, elucidation of the regulatory mechanisms of miRNAs in peripheral B cells will contribute to a fu...

Regulation of the ovarian oxidative status by leptin during the ovulatory process in rats

“…These results are supported by previous studies that demonstrated that similar daily administrations with leptin reduce the incidence of follicular apoptosis after 7 days of leptin injection and that leptin may be involved in accelerating follicular maturation by attenuating follicular atresia through an increase in the BCL2/BAX ratio (Almog et al 2001). In addition, using different in vitro systems, other authors have found that leptin reduces apoptosis and induces cell proliferation, at least in part, by upregulating BCL2 expression (Brown & Dunmore 2007, Sirotkin & Grossmann 2007, Lam et al 2010, and that leptin may act as an anti-apoptotic factor in luteinized porcine granulosa cells by increasing BCL2 expression and decreasing caspase 3 activity (Dineva et al 2007). It is noteworthy that neither the acute nor the daily treatment altered procaspase 3 expression.…”

Role of Central Leptin Signaling in the Starvation-Induced Alteration of B-Cell Development

“…It is known that leptin-deficient ob/ob mice exhibit the immunological changes similar to those induced by starvation, i.e., thymic atrophy and decreased maturation of T and B cells (Howard et al, 1999;Claycombe et al, 2008;Lam et al, 2010). Because serum leptin concentrations are rapidly lowered by starvation (Ahima et al, 1996), it is conceivable that leptin plays a role in the starvation-induced immunodeficiency.…”

New developments in the pathology of malignant lymphoma. A review of the literature published from August 2010–October 2010

“…MYC suppresses multiple miRNAs in lymphoma cells. Lam et al [9] found, however, that Dicer and MYC have no synergistic effect on lymphoma development, but rather the opposite. Deletion of Dicer in established B-cell lymphomas resulted in apoptosis, revealing that Dicer is required for B-cell lymphoma survival.…”