Punnonen J, Cocks B G, de Vries J E
DNAX Research Institute of Molecular and Cellular Biology, Human Immunology Department, Palo Alto, CA 94304, USA.
J Immunol. 1995 Nov 1;155(9):4248-54.
The present study demonstrates that IL-4 induces germ-line IgE heavy chain (epsilon) gene transcription in human fetal splenic mononuclear cells; fetal bone marrow cells; highly purified sorted surface (s) mu+, CD10+, CD19+ immature B cells; and s mu-, cytoplasmic mu+, CD10+, CD19+ pre-B cells derived from human fetal bone marrow. Similar to observations in normal adult B cells, TGF-beta and IFN-gamma inhibited IL-4-induced germ-line epsilon RNA synthesis in fetal pre-B cells, whereas anti-CD40 mAbs and TNF-alpha had enhancing effects, suggesting that the general mechanisms regulating germ-line epsilon transcription in adult B cells and pre-B cells are similar. IL-13 also induced germ-line epsilon RNA synthesis in s mu+, CD10+, CD19+ immature B cells, but the level of transcription induced by IL-13 was significantly less than that induced by IL-4. Anti-CD40 mAbs strongly synergized with both IL-4 and IL-13 in inducing germ-line epsilon RNA synthesis by fetal immature B cells. Interestingly, IL-13 failed to induce germ-line epsilon RNA synthesis in s mu- pre-B cells even in the presence of anti-CD40 mAbs. These distinct effects of IL-4 and IL-13 suggest that functional IL-13R are expressed at a later stage of B cell ontogeny than IL-4R, and that IL-13, in contrast to IL-4, does not regulate pre-B cell differentiation. Given the fact that IL-4 production appears to be enhanced in atopic individuals, the capacity of IL-4 to induce germ-line epsilon transcription in human fetal immature B cells and pre-B cells suggests that commitment of B cell precursors to IgE-producing cells may occur during intrauterine life and may explain the increased IgE production in neonates with a family history of atopy.
本研究表明，白细胞介素-4（IL-4）可诱导人胎儿脾单核细胞、胎儿骨髓细胞、高度纯化分选的表面（s）μ⁺、CD10⁺、CD19⁺未成熟B细胞以及源自人胎儿骨髓的sμ⁻、胞质μ⁺、CD10⁺、CD19⁺前B细胞中的种系IgE重链（ε）基因转录。与在正常成人B细胞中的观察结果相似，转化生长因子-β（TGF-β）和干扰素-γ（IFN-γ）抑制胎儿前B细胞中IL-4诱导的种系εRNA合成，而抗CD40单克隆抗体和肿瘤坏死因子-α（TNF-α）具有增强作用，这表明调节成人B细胞和前B细胞中种系ε转录的一般机制是相似的。白细胞介素-13（IL-13）也可诱导sμ⁺、CD10⁺、CD19⁺未成熟B细胞中的种系εRNA合成，但IL-13诱导的转录水平明显低于IL-4诱导的水平。抗CD40单克隆抗体在诱导胎儿未成熟B细胞种系εRNA合成方面与IL-4和IL-13均有强烈协同作用。有趣的是，即使存在抗CD40单克隆抗体，IL-13也无法诱导sμ⁻前B细胞中的种系εRNA合成。IL-4和IL-13的这些不同作用表明，功能性IL-13受体在B细胞个体发育中的表达阶段比IL-4受体晚，并且与IL-4相反，IL-13不调节前B细胞分化。鉴于特应性个体中IL-4的产生似乎增强，IL-4在人胎儿未成熟B细胞和前B细胞中诱导种系ε转录的能力表明，B细胞前体向产生IgE细胞的定向分化可能在子宫内生活期间发生，并且可能解释有特应性家族史的新生儿中IgE产生增加的现象。
