Hata D, Kawakami Y, Inagaki N, Lantz C S, Kitamura T, Khan W N, Maeda-Yamamoto M, Miura T, Han W, Hartman S E, Yao L, Nagai H, Goldfeld A E, Alt F W, Galli S J, Witte O N, Kawakami T
Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
J Exp Med. 1998 Apr 20;187(8):1235-47. doi: 10.1084/jem.187.8.1235.
We investigated the role of Bruton's tyrosine kinase (Btk) in FcepsilonRI-dependent activation of mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell development is apparently normal in these btk mutant mice. However, mast cells derived from these mice exhibited significant abnormalities in FcepsilonRI-dependent function. xid mice primed with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo. Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or btk null mice exhibited mild impairments in degranulation, and more profound defects in the production of several cytokines, upon FcepsilonRI cross-linking. Moreover, the transcriptional activities of these cytokine genes were severely reduced in FcepsilonRI-stimulated btk mutant mast cells. The specificity of these effects of btk mutations was confirmed by the improvement in the ability of btk mutant mast cells to degranulate and to secrete cytokines after the retroviral transfer of wild-type btk cDNA, but not of vector or kinase-dead btk cDNA. Retroviral transfer of Emt (= Itk/Tsk), Btk's closest relative, also partially improved the ability of btk mutant mast cells to secrete mediators. Taken together, these results demonstrate an important role for Btk in the full expression of FcepsilonRI signal transduction in mast cells.
我们使用xid和btk基因敲除突变小鼠，研究了布鲁顿酪氨酸激酶（Btk）在小鼠肥大细胞的FcepsilonRI依赖性激活中的作用。与B细胞发育不同，这些btk突变小鼠的肥大细胞发育明显正常。然而，源自这些小鼠的肥大细胞在FcepsilonRI依赖性功能方面表现出显著异常。用抗二硝基苯基单克隆IgE抗体致敏的xid小鼠在体内受到抗原刺激时，早期过敏反应略有减弱，晚期过敏反应则严重减弱。与此发现一致，源自xid或btk基因敲除小鼠骨髓细胞的培养肥大细胞在FcepsilonRI交联后，脱颗粒功能有轻度受损，几种细胞因子的产生有更严重的缺陷。此外，在FcepsilonRI刺激的btk突变肥大细胞中，这些细胞因子基因的转录活性严重降低。通过逆转录病毒转染野生型btk cDNA（而非载体或激酶失活的btk cDNA）后，btk突变肥大细胞脱颗粒和分泌细胞因子的能力得到改善，从而证实了btk突变这些效应的特异性。btk的近亲Emt（=Itk/Tsk）的逆转录病毒转染也部分改善了btk突变肥大细胞分泌介质的能力。综上所述，这些结果证明了Btk在肥大细胞FcepsilonRI信号转导的充分表达中起重要作用。
