title: 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.
authors.affiliation: Department of Pathology and Centre of Infection and Immunology, University of Hong Kong, Hong Kong, China.
authors.forename: Queenie Lai Kwan
authors.initials: QL
authors.lastname: Lam
authors.forename: Shengjun
authors.initials: S
authors.lastname: Wang
authors.forename: Otis King Hung
authors.initials: OK
authors.lastname: Ko
authors.forename: Paul W
authors.initials: PW
authors.lastname: Kincade
authors.forename: Liwei
authors.initials: L
authors.lastname: Lu
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D020738:Leptin / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology*; D054411:Receptors, Leptin / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; C530105:Ccnd1 protein, mouse; D020738:Leptin; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D019938:Cyclin D1