Dynamique des Intéractions Membranaires Normales et Pathologiques, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5235, Montpellier, France.
J Immunol. 2010 Dec 1;185(11):6774-82. doi: 10.4049/jimmunol.1000549. Epub 2010 Nov 3.
The zebrafish genome contains a large number of genes encoding potential cytokine receptor genes as judged by homology to mammalian receptors. The sequences are too divergent to allow unambiguous assignments of all receptors to specific cytokines, and only a few have been assigned functions by functional studies. Among receptors for class II helical cytokines-i.e., IFNs that include virus-induced Ifns (Ifn-) and type II Ifns (Ifn-γ), together with Il-10 and its related cytokines (Il-20, Il-22, and Il-26)-only the Ifn--specific complexes have been functionally identified, whereas the receptors for the two Ifn-γ (Ifn-γ1 and Ifn-γ2) are unknown. In this work, we identify conditions in which Ifn-γ1 and Ifn-γ2 (also called IFNG or IFN-γ and IFN-gammarel) are induced in fish larvae and adults. We use morpholino-mediated loss-of-function analysis to screen candidate receptors and identify the components of their receptor complexes. We find that Ifn-γ1 and Ifn-γ2 bind to different receptor complexes. The receptor complex for Ifn-γ2 includes cytokine receptor family B (Crfb)6 together with Crfb13 and Crfb17, whereas the receptor complex for Ifn-γ1 does not include Crfb6 or Crfb13 but includes Crfb17. We also show that of the two Jak2 paralogues present in the zebrafish Jak2a but not Jak2b is involved in the intracellular transmission of the Ifn-γ signal. These results shed new light on the evolution of the Ifn-γ signaling in fish and tetrapods and contribute toward an integrated view of the innate immune regulation in vertebrates.
斑马鱼基因组包含大量编码潜在细胞因子受体基因的序列，这些序列与哺乳动物受体具有同源性。由于序列差异太大，无法将所有受体明确分配给特定的细胞因子，只有少数通过功能研究被赋予了功能。在 II 类螺旋细胞因子（即包括病毒诱导的 Ifn-α 和 II 型 Ifn-γ 在内的 IFN）、IL-10 及其相关细胞因子（IL-20、IL-22 和 IL-26）的受体中，只有 IFN-α 特异性复合物的功能已被确定，而两种 IFN-γ（IFN-γ1 和 IFN-γ2）的受体尚不清楚。在这项工作中，我们鉴定了在鱼类幼虫和成鱼中诱导 IFN-γ1 和 IFN-γ2（也称为 IFNG 或 IFN-γ 和 IFN-γrel）的条件。我们使用基于 morpholino 的功能丧失分析筛选候选受体，并鉴定其受体复合物的组成部分。我们发现 IFN-γ1 和 IFN-γ2 结合到不同的受体复合物上。IFN-γ2 的受体复合物包括细胞因子受体家族 B（Crfb）6 与 Crfb13 和 Crfb17，而 IFN-γ1 的受体复合物不包括 Crfb6 或 Crfb13，但包括 Crfb17。我们还表明，在斑马鱼中存在的两个 Jak2 旁系同源物 Jak2a 而不是 Jak2b 参与了 IFN-γ 信号的细胞内转导。这些结果为鱼类和四足动物中 IFN-γ 信号的进化提供了新的线索，并为脊椎动物固有免疫调节提供了一个综合的观点。
