Case Comprehensive Cancer Center and Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
J Biol Chem. 2011 Jun 10;286(23):20606-14. doi: 10.1074/jbc.M110.216549. Epub 2011 Apr 20.
The lipocalin mouse 24p3 has been implicated in diverse physiological processes, including apoptosis, iron trafficking, development and innate immunity. Studies from our laboratory as well as others demonstrated the proapoptotic activity of 24p3 in a variety of cultured models. However, a general role for the lipocalin 24p3 in the hematopoietic system has not been tested in vivo. To study the role of 24p3, we derived 24p3 null mice and back-crossed them onto C57BL/6 and 129/SVE backgrounds. Homozygous 24p3(-/-) mice developed a progressive accumulation of lymphoid, myeloid, and erythroid cells, which was not due to enhanced hematopoiesis because competitive repopulation and recovery from myelosuppression were the same as for wild type. Instead, apoptotic defects were unique to many mature hematopoietic cell types, including neutrophils, cytokine-dependent mast cells, thymocytes, and erythroid cells. Thymocytes isolated from 24p3 null mice also displayed resistance to apoptosis-induced by dexamethasone. Bim response to various apoptotic stimuli was attenuated in 24p3(-/-) cells, thus explaining their resistance to the ensuing cell death. The results of these studies, in conjunction with those of previous studies, reveal 24p3 as a regulator of the hematopoietic compartment with important roles in normal physiology and disease progression. Interestingly, these functions are limited to relatively mature blood cell compartments.
鼠 24p3 脂联素参与多种生理过程,包括细胞凋亡、铁运输、发育和先天免疫。我们实验室和其他实验室的研究表明,24p3 在各种培养模型中具有促凋亡活性。然而,脂联素 24p3 在造血系统中的一般作用尚未在体内进行测试。为了研究 24p3 的作用,我们制备了 24p3 缺失小鼠,并将其回交至 C57BL/6 和 129/SVE 背景下。纯合 24p3(-/-) 小鼠逐渐积累淋巴样、髓样和红细胞,这不是由于造血增强所致,因为竞争再定植和骨髓抑制的恢复与野生型相同。相反,凋亡缺陷是许多成熟造血细胞类型所特有的,包括中性粒细胞、细胞因子依赖性肥大细胞、胸腺细胞和红细胞。从 24p3(-/-) 小鼠分离的胸腺细胞也显示出对地塞米松诱导的凋亡的抗性。24p3(-/-) 细胞中对各种凋亡刺激的 Bim 反应减弱,从而解释了它们对随后的细胞死亡的抗性。这些研究结果与之前的研究结果一起,揭示了 24p3 作为造血区室的调节剂,在正常生理和疾病进展中具有重要作用。有趣的是,这些功能仅限于相对成熟的血细胞区室。