Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and Cyclin D1.
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.
Lam
Queenie Lai Kwan
QL
Department of Pathology and Centre of Infection and Immunology, University of Hong Kong, Hong Kong, China.
Wang
Shengjun
S
Ko
Otis King Hung
OK
Kincade
Paul W
PW
Lu
Liwei
L
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
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