hsBAFF promotes proliferation and survival in cultured B lymphocytes via calcium signaling activation of mTOR pathway

• Published in: Cytokine (Philadelphia, Pa.) Pa.), 2013-05, Vol.62 (2), p.310-321
• Main Authors: Ke, Zhen, Liang, Dingfang, Zeng, Qingyu, Ren, Qian, Ma, Hongwei, Gui, Lin, Chen, Sujuan, Guo, Min, Xu, Yijiao, Gao, Wei, Zhang, Shuangquan, Chen, Long
• Format: Article
• Language: English
• Subjects: Animals; autoimmune diseases; B lymphocyte; B-Cell Activating Factor - metabolism; B-lymphocytes; B-Lymphocytes - metabolism; B-Lymphocytes - physiology; Boron Compounds - chemistry; Calcium - metabolism; Calcium ion; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - chemistry; CaMKII; cell growth; Cell Proliferation - drug effects; Cell Survival; Cells, Cultured; chelating agents; Chelating Agents - pharmacology; cytokines; Egtazic Acid - analogs & derivatives; Egtazic Acid - pharmacology; Enzyme Activation; Human soluble BAFF; Humans; Immunosuppressive Agents - pharmacology; Lymphocyte Activation - drug effects; lymphocyte proliferation; mammals; Mice; Mice, Inbred ICR; mTOR; pathogenesis; phosphorylation; protein kinases; Sirolimus - pharmacology; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2013.03.011

•hsBAFF-induced extracellular Ca2+ influx and ER Ca2+ release elevates [Ca2+]i.•hsBAFF-elevated [Ca2+]i activates mTOR signaling in B lymphocytes.•hsBAFF-elevated [Ca2+]i elicits CaMKII phosphorylation in B lymphocytes.•hsBAFF-increased CaMKII phosphorylation activates mTOR signaling in B lymphocytes.•hsBAFF promotes B cell growth and survival via Ca2+/CaMKII/mTOR signaling pathway. B-cell activating factor of the TNF family (BAFF, also called BLyS, TALL-1, THANK, or zTNF4) has revealed its critical function in B lymphocyte proliferation and survival, as well as the pathogenesis of autoimmune disease. However, the molecular mechanisms of excess BAFF-extended aggressive B lymphocytes have not been completely defined. Here we show that excessive hsBAFF-elevated [Ca2+]i activated mammalian target of rapamycin (mTOR) signaling pathway, leading to proliferation and survival in B lymphocytes. This is supported by the findings that intracellular Ca2+ chelator (BAPTA/AM) or mTOR inhibitor (rapamycin) abolished the events. Sequentially, we observed that preventing [Ca2+]i elevation using EGTA or 2-APB dramatically inhibited hsBAFF activation of mTOR signaling, as well as cell growth and survival, suggesting that hsBAFF-induced extracellular Ca2+ influx and ER Ca2+ release elevates [Ca2+]i contributing to B lymphocyte proliferation and survival via activation of mTOR signaling. Further, we noticed that pretreatment with BAPTA/AM, EGTA or 2-APB blocked hsBAFF-increased phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII), and inhibiting CaMKII with KN93 attenuated hsBAFF-activated mTOR signaling, as well as cell growth and survival, revealing that the effects of hsBAFF-elevated [Ca2+]i on mTOR signaling as well as proliferation and survival in B lymphocytes is through stimulating phosphorylation of CaMKII. The results indicate that hsBAFF activates mTOR pathway triggering B lymphocyte proliferation and survival by calcium signaling. Our findings suggest that manipulation of intracellular Ca2+ level or CaMKII and mTOR activity may be exploited for the prevention of excessive BAFF-induced aggressive B lymphocyte disorders and autoimmune diseases.