Dickensheets H L, Donnelly R P
Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
J Immunol. 1997 Dec 15;159(12):6226-33.
The Th2-type cytokines IL-4 and IL-13 induce expression of a distinct subset of genes in human monocytes. These include Fc epsilonRII (CD23), 15-lipoxygenase, IL-1 receptor antagonist (IL-1ra), and type I and type II IL-1 receptors (IL-1R). IFN-gamma has been shown to inhibit induction of CD23 and 15-lipoxygenase in monocytes; however, the effects of IFN-gamma on type I and type II IL-1R gene expression have not been defined. We examined the effects of IFN-gamma on both basal and IL-4/IL-13-induced IL-1R gene expression in primary monocytes. IL-4 and IL-13 induced dose- and time-dependent increases in IL-1RI and IL-1RII mRNA levels. IFN-gamma decreased basal expression as well as the induction of these genes by IL-4 and IL-13. Inhibition of IL-1RI and IL-1RII mRNA levels by IFN-gamma was transcriptionally mediated, and correlated directly with decreased production of soluble IL-1RII. Furthermore, the ability to suppress IL-1RI and IL-1RII mRNA levels was not unique to IFN-gamma because IL-10 also inhibited expression of these genes in IL-4/IL-13-stimulated monocytes. Inhibition of IL-1R gene expression by IFN-gamma and IL-10 was not due to down-regulation of surface IL-4R because pretreatment with these cytokines did not decrease the number of IL-4 binding sites per cell. However, suppression of IL-1R gene expression by IFN-gamma and IL-10 was associated with decreased tyrosine phosphorylation and nuclear translocation of the IL-4/IL-13-inducible transcription factor, Stat6, suggesting a potential mechanism by which IFN-gamma and IL-10 may mediate their suppressive effects. These findings demonstrate that certain cytokines, including IFN-gamma and IL-10, antagonize the ability of IL-4 and IL-13 to induce increased expression of the IL-1RI and IL-1RII genes in monocytes.
Th2型细胞因子白细胞介素-4（IL-4）和白细胞介素-13（IL-13）可诱导人单核细胞中一组独特基因的表达。这些基因包括FcεRII（CD23）、15-脂氧合酶、白细胞介素-1受体拮抗剂（IL-1ra）以及I型和II型白细胞介素-1受体（IL-1R）。已有研究表明，干扰素-γ（IFN-γ）可抑制单核细胞中CD23和15-脂氧合酶的诱导表达；然而，IFN-γ对I型和II型IL-1R基因表达的影响尚未明确。我们研究了IFN-γ对原代单核细胞中基础状态以及IL-4/IL-13诱导的IL-1R基因表达的影响。IL-4和IL-13可诱导IL-1RI和IL-1RII mRNA水平呈剂量和时间依赖性增加。IFN-γ可降低基础表达水平以及IL-4和IL-13对这些基因的诱导表达。IFN-γ对IL-1RI和IL-1RII mRNA水平的抑制作用是由转录介导的，并且与可溶性IL-1RII产生的减少直接相关。此外，抑制IL-1RI和IL-1RII mRNA水平并非IFN-γ所特有，因为IL-10也可抑制IL-4/IL-13刺激的单核细胞中这些基因的表达。IFN-γ和IL-10对IL-1R基因表达的抑制并非由于表面IL-4R的下调，因为用这些细胞因子预处理并未减少每个细胞上IL-4结合位点的数量。然而，IFN-γ和IL-10对IL-1R基因表达的抑制与IL-4/IL-13诱导的转录因子Stat6的酪氨酸磷酸化和核转位减少有关，这提示了IFN-γ和IL-10可能介导其抑制作用的潜在机制。这些发现表明，某些细胞因子，包括IFN-γ和IL-10，可拮抗IL-4和IL-13诱导单核细胞中IL-1RI和IL-1RII基因表达增加的能力。
