Characterization of Novel Interleukin 10 Related Genes

总结：细菌内毒素、脂多糖（LPS）激活人单核细胞，可诱导多种细胞因子的表达，包括肿瘤坏死因子（TNF）、白细胞介素-1（IL-1）、IL-6和IL-10。 IL-10的表达相对于TNF、IL-1和IL-6的表达延迟。 此外，IL-10反馈抑制TNF、IL-1和IL-6的表达，从而提供了用于控制单核细胞中促炎细胞因子产生的有效自分泌机制。 在这个项目中，我们正在研究IL-10下调内毒素刺激的单核细胞中TNF和IL-1等细胞因子产生的机制。 我们还评估了IL-10对由细胞因子如IFN-γ（IFN-g）和IL-4激活的信号转导事件的影响。 我们已经发现IL-10抑制由IL-4和IFN-γ诱导的活化和基因表达。 我们还确定了IL-10抑制IL-4诱导型基因表达的能力是IL-4诱导型转录因子STAT6酪氨酸磷酸化和核转位减少的结果。 我们现在正在研究一个新的JAK/STAT抑制基因家族，细胞因子信号转导抑制因子（SOCS）基因，在介导这些IL-10诱导的抑制作用中的作用。 我们已经发现IL-10选择性地诱导这个新鉴定的基因家族的一个成员SOCS-3的表达。 在巨噬细胞系中SOCS-3的强制表达显著抑制了几种细胞因子（包括IFN-γ、GM-CSF和IL-4）对STAT活性的诱导。 因此，IL-10拮抗精氨酸诱导基因表达的能力似乎与其诱导SOCS-3基因快速表达的能力相关。 在相关的研究中，我们也在研究几种新鉴定的IL-10同源物的生物活性。 其中之一IL-19与IL-10具有约21%的氨基酸同源性，并且可以利用形成功能性IL-10受体复合物的两条受体链中的至少一条。 我们已经发现IL-19基因的表达被许多诱导单核细胞中IL-10基因表达的相同试剂上调。 然而，与IL-10基因不同，IL-19在活化的T细胞中不表达。 另一种IL-10同源物IL-TIF（IL-10相关T细胞衍生的诱导因子）最近也被描述。 我们与新泽西医学与牙科大学（UMDNJ）的科学家一起，鉴定并表征了编码这种新型IL-10相关细胞因子IL-TIF受体配体结合链的基因。 该受体链与IL-10R-β链（IL-10R2）异二聚化，形成功能性IL-TIF受体复合物。 因此，IL-10R2是IL-10和IL-TIF受体两者的组分。 我们最近发现IL-TIF受体在肝脏和肾脏中以高水平表达，但在造血组织如脾脏和胸腺中不表达。 这表明该受体在调节这些组织中的基因表达方面可能具有功能作用。

Summary: Activation of human monocytes by bacterial endotoxin, lipopolysaccharide (LPS), induces expression of many cytokines, including tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6 and IL-10. IL-10 expression is delayed relative to that of TNF, IL-1 and IL-6. Furthermore, IL-10 feedback inhibits expression of TNF, IL-1 and IL-6, thus providing an efficient autocrine mechanism for controlling proinflammatory cytokine production in monocytes. In this project, we are examining the mechanism by which IL-10 down-regulates production of cytokines such as TNF and IL-1 in endotoxin-stimulated monocytes. We are also evaluating the effects of IL-10 on signal transduction events that are activated by cytokines such as IFN-gamma (IFN-g) and IL-4. We have found that IL-10 inhibits activation and gene expression induced by IL-4 and IFN-gamma. We have also determined that the ability of IL-10 to inhibit IL-4-inducible gene expression is a consequence of decreased tyrosine phosphorylation and nuclear translocation of the IL-4-inducible transcription factor, STAT6. We are now examining the role of a novel family of JAK/STAT inhibitory genes, the Suppressors of Cytokine Signaling (SOCS) genes, in mediating these IL-10-inducible inhibitory effects. We have found that IL-10 selectively induces expression of one member of this newly identified gene family, SOCS-3. Forced expression of SOCS-3 in a macrophage cell line markedly inhibits induction of STAT activity by several cytokines, including IFN-gamma, GM-CSF and IL-4. Therefore, the ability of IL-10 to antagonize cytokine-inducible gene expression appears to be associated with its ability to induce rapid expression of the SOCS-3 gene. In related studies, we are also examining the biological activities of several newly identified IL-10 homologues. One of these, IL-19, shares approximately 21% amino acid homology with IL-10, and may utilize at least one of the two receptor chains that form the functional IL-10 receptor complex. We have found that expression of the IL-19 gene is upregulated by many of the same agents that induce IL-10 gene expression in monocytes. However, unlike the IL-10 gene, IL-19 is not expressed in activated T cells. Another IL-10 homologue, IL-TIF (IL-10-related T cell-derived inducible factor), has also recently been described. Together with scientists at the University of Medicine & Dentistry of New Jersey (UMDNJ), we have identified and characterized the gene encoding the ligand-binding chain of the receptor for this novel IL-10-related cytokine, IL-TIF. This receptor chain heterodimerizes with the IL-10R-beta chain (IL-10R2) to form a functional IL-TIF receptor complex. Therefore, IL-10R2 is component of both the IL-10 and IL-TIF receptors. We have recently found that the IL-TIF receptor is expressed at high levels in liver and kidney, but not in hematopoietic tissues such as the spleen and thymus. This suggests a possible functional role for this receptor in regulating gene expression in these tissues.