Parrish-Novak Julia, Xu Wenfeng, Brender Ty, Yao Lena, Jones Crystal, West Jim, Brandt Cameron, Jelinek Laura, Madden Karen, McKernan Patricia A, Foster Donald C, Jaspers Stephen, Chandrasekher Yasmin A
Department of Cytokine and Receptor Biology, ZymoGenetics, Inc., Seattle, Washington 98102, USA.
J Biol Chem. 2002 Dec 6;277(49):47517-23. doi: 10.1074/jbc.M205114200. Epub 2002 Sep 25.
Cytokines that signal through Class II receptors form a distinct family that includes the interferons and interleukin 10 (IL-10). Recent identification of several IL-10 homologs has defined a cytokine subfamily that includes AK155, IL-19, IL-20, IL-22, and IL-24. Within this subfamily, IL-19, IL-20, and IL-24 exhibit substantial sharing of receptor complexes; all three are capable of signaling through IL-20RA/IL-20RB, and IL-20 and IL-24 both can also use IL-22R/IL-20RB. However, the biological effects of these three cytokines appear quite distinct: immune activity with IL-19, skin biology with IL-20, and tumor apoptosis with IL-24. To more fully elucidate their interactions with the receptor complexes, we have performed a series of in vitro assays. Reporter, proliferation, and direct STAT activation assays using cell lines expressing transfected receptors revealed differences between the receptor complexes. IL-19 and IL-24 also exhibited growth inhibition on a cell line endogenously expressing all three receptor subunits, an effect that was seen at cytokine levels two orders of magnitude above those required for STAT activation or proliferation. These results demonstrate that, although this subclass exhibits receptor complex redundancy, there are differences in ligand/receptor interactions and in signal transduction that may lead to specificity and a distinct biology for each cytokine.
通过II类受体发出信号的细胞因子构成一个独特的家族,其中包括干扰素和白细胞介素10(IL-10)。最近对几种IL-10同源物的鉴定确定了一个细胞因子亚家族,其中包括AK155、IL-19、IL-20、IL-22和IL-24。在这个亚家族中,IL-19、IL-20和IL-24在受体复合物方面有大量共享;这三种细胞因子都能够通过IL-20RA/IL-20RB发出信号,并且IL-20和IL-24都还可以利用IL-22R/IL-20RB。然而,这三种细胞因子的生物学效应似乎截然不同:IL-19具有免疫活性,IL-20与皮肤生物学有关,而IL-24则与肿瘤凋亡有关。为了更全面地阐明它们与受体复合物的相互作用,我们进行了一系列体外试验。使用表达转染受体的细胞系进行的报告基因、增殖和直接STAT激活试验揭示了受体复合物之间的差异。IL-19和IL-24对一个内源性表达所有三种受体亚基的细胞系也表现出生长抑制作用,这种效应在细胞因子水平比STAT激活或增殖所需水平高两个数量级时就能看到。这些结果表明,尽管这个亚类表现出受体复合物冗余,但配体/受体相互作用和信号转导存在差异,这可能导致每种细胞因子具有特异性和独特的生物学特性。