Junttila Ilkka S, Mizukami Kiyoshi, Dickensheets Harold, Meier-Schellersheim Martin, Yamane Hidehiro, Donnelly Raymond P, Paul William E
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Exp Med. 2008 Oct 27;205(11):2595-608. doi: 10.1084/jem.20080452. Epub 2008 Oct 13.
Interleukin (IL)-4 and -13 are related cytokines sharing functional receptors. IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. In this study, we show that mouse bone marrow-derived macrophages and human and mouse monocytes showed a much greater sensitivity to IL-4 than to IL-13. Lack of functional gammac made these cells poorly responsive to IL-4, while retaining full responsiveness to IL-13. In mouse peritoneal macrophages, IL-4 potency exceeds that of IL-13, but lack of gammac had only a modest effect on IL-4 signaling. In contrast, IL-13 stimulated greater responses than IL-4 in fibroblasts. Using levels of receptor chain expression and known binding affinities, we modeled the assemblage of functional type I and II receptor complexes. The differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac accounted for the distinct IL-4-IL-13 sensitivities of the various cell types. These findings provide an explanation for IL-13's principal function as an "effector" cytokine and IL-4's principal role as an "immunoregulatory" cytokine.
白细胞介素（IL）-4和-13是共享功能受体的相关细胞因子。IL-4通过I型（IL-4Rα/共同γ链[γc]）和II型（IL-4Rα/-13Rα1）IL-4受体发出信号，而IL-13仅利用II型受体。在本研究中，我们表明小鼠骨髓来源的巨噬细胞以及人和小鼠单核细胞对IL-4的敏感性远高于对IL-13的敏感性。缺乏功能性γc使这些细胞对IL-4反应不佳，而对IL-13仍保持完全反应性。在小鼠腹腔巨噬细胞中，IL-4的效力超过IL-13，但缺乏γc对IL-4信号传导仅有适度影响。相反，在成纤维细胞中，IL-13比IL-4刺激产生更大的反应。利用受体链表达水平和已知的结合亲和力，我们模拟了功能性I型和II型受体复合物的组装。IL-4Rα、IL-13Rα1和γc的差异表达解释了各种细胞类型对IL-4-IL-13的不同敏感性。这些发现为IL-13作为“效应”细胞因子的主要功能以及IL-4作为“免疫调节”细胞因子的主要作用提供了解释。
