Blum H, Wolf M, Enssle K, Röllinghoff M, Gessner A
Institute of Clinical Microbiology and Immunology, University of Erlangen-Nurnberg, Germany.
J Immunol. 1996 Sep 1;157(5):1846-53.
The IL-4R exists in two forms, either membrane bound or as a soluble (s) molecule. Since the sIL-4R binds to its ligand with high affinity, thereby acting as an immunoregulatory molecule, we were interested in the processes leading to its release. First, the release of sIL-4R in the model of murine leishmaniosis was analyzed. Infection of mice with Leishmania major resulted in up-regulation of sIL-4R production by Ag-stimulated CD4+ T cells, with a maximum around 7 days after infection. To clarify the mechanisms underlying sIL-4R release, in vitro studies were performed. After stimulation of naive lymphoid cells with IL-4, sIL-4R release was dependent on up-regulation of spliced IL-4R mRNA, as shown by inhibition with specific antisense oligonucleotides. In contrast to this, no increase in the spliced IL-4R mRNA and no inhibitory influence of antisense oligonucleotides were observed after stimulation of T cells from IL-4-deficient mice with anti-CD3 mAb. Thus, TCR stimulation can lead to IL-4-independent sIL-4R production. Under these conditions proteolytic shedding of membrane-bound IL-4R appears to be the principal mechanism of release, since in contrast to stimulation with IL-4, iodinated sIL-4R could only be immunoprecipitated after cell surface labeling and subsequent TCR stimulation. The common gamma-chain, a component of the IL-4R complex, did not appear to be involved in the pathways leading to sIL-4R expression. This analysis suggests the existence of two differentially regulated pathways of sIL-4R release, possibly having different consequences for the regulation of IL-4 bioactivity.
白细胞介素-4受体（IL-4R）以两种形式存在，即膜结合形式或可溶性（s）分子形式。由于可溶性IL-4R（sIL-4R）能与其配体高亲和力结合，从而作为一种免疫调节分子发挥作用，因此我们对其释放过程很感兴趣。首先，分析了小鼠利什曼病模型中sIL-4R的释放情况。用硕大利什曼原虫感染小鼠后，抗原刺激的CD4⁺T细胞产生的sIL-4R上调，在感染后约7天达到峰值。为阐明sIL-4R释放的潜在机制，进行了体外研究。用白细胞介素-4刺激幼稚淋巴细胞后，sIL-4R的释放依赖于剪接的IL-4R mRNA的上调，这通过特异性反义寡核苷酸抑制得以证明。与此相反，用抗CD3单克隆抗体刺激白细胞介素-4缺陷小鼠的T细胞后，未观察到剪接的IL-4R mRNA增加，也未观察到反义寡核苷酸的抑制作用。因此，T细胞受体（TCR）刺激可导致不依赖白细胞介素-4的sIL-4R产生。在这些条件下，膜结合型IL-4R的蛋白水解脱落似乎是释放的主要机制，因为与白细胞介素-4刺激不同，碘化的sIL-4R只有在细胞表面标记并随后进行TCR刺激后才能被免疫沉淀。白细胞介素-4受体复合物的组成成分共同γ链似乎不参与导致sIL-4R表达的途径。该分析表明存在两条差异调节的sIL-4R释放途径，可能对白细胞介素-4生物活性的调节产生不同影响。
