Role of PI3-kinase in the development and function of mast cells

用p85α-缺陷小鼠研究I_A类PI3K在肥大细胞分化中的作用。我们发现p85α-缺陷小鼠选择性地缺乏胃肠道和腹膜肥大细胞，而肥大细胞在正常生理条件下很容易在皮肤等其他组织中发现。我们研究了为什么p85α-缺陷小鼠只缺乏胃肠道肥大细胞。我们首先用极限稀释法检测骨髓、脾脏和肠道肥大细胞前体细胞频率。结果表明，肠道内的前体频率低于野生型的10%，而骨髓和脾脏的前体频率与野生型小鼠相比未受影响。这些结果表明，p85α-缺陷小鼠的肠道内祖细胞和/或成熟肥大细胞的存活或前体细胞向肠道的迁移受到损害。我们发现，在含有IL-3的骨髓中培养的p85α-缺陷肥大细胞中，c-Kit信号严重受损，而在培养的p85α-缺陷肥大细胞中，对SCF的增殖和JNK激活严重受损。我们还研究了已知在细胞迁移中重要的整合素的表达和功能。我们发现，在p85α-缺陷肥大细胞中，α4β7整合素的表达正常，但α4β7与其配体MAdCAM的结合明显弱于野生型肥大细胞。我们从这些观察中得出结论，p85α-缺陷小鼠胃肠道肥大细胞的缺乏是由于向肠道的迁移和在肠道中的存活不足。

Role of class I_A PI3K in mast cell differentiation was examined using p85α-deficient mice. We have found that p85α-deficient mice selectively lack gastrointestinal and peritoneal mast cells whereas mast cells are readily found in other tissues such as skin under normal physiological conditions. We studied why p85α-deficient mice lack only gastrointestinal mast cells. We first examined the mast cell precursor frequency in the bone marrow, spleen and intestinal tract, by limiting dilution method. It was revealed that the precursor frequency in the intestine was less than 10% of wild type level whereas those of the bone marrow and spleen were unaffected compared to wild type mice. These results suggest that either the survival of progenitors and/or mature mast cell in the intestine or the migration of precursor cells to the intestine is impaired in p85α-deficient mice. We found that c-Kit signal is strongly impaired in p85α-deficient mast cells established from the bone marrow with IL-3 as proliferation and JNK activation in response to SCF was severely impaired in p85α-deficient cultured mast cells. We also examined the expression and function of integrins that are known to be important in cell migration. We found that expression of α4β7 integrin that is critical for cellular migration to the intestine was normal in p85α-deficient mast cells but the binding of α4β7 to its ligand, MAdCAM was significantly weaker than that of wild type mast cells. We conclude from these observations that the lack of gastrointestinal mast cells in p85α-deficient mice is due to the deficiency in both migration to and survival in the intestine.