DIFFERENTIAL EXPRESSION OF INTERFERON REGULATORY FACTOR-1 (IRF-1), IRF-2, AND INTERFERON CONSENSUS SEQUENCE BINDING-PROTEIN GENES IN LIPOPOLYSACCHARIDE (LPS)-RESPONSIVE AND LPS-HYPORESPONSIVE MACROPHAGES
DIFFERENTIAL EXPRESSION OF INTERFERON REGULATORY FACTOR-1 (IRF-1), IRF-2, AND INTERFERON CONSENSUS SEQUENCE BINDING-PROTEIN GENES IN LIPOPOLYSACCHARIDE (LPS)-RESPONSIVE AND LPS-HYPORESPONSIVE MACROPHAGES
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DOI：
10.1128/iai.63.2.601-608.1995
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发表时间：
1995-02-01
影响因子：
3.1
通讯作者：
VOGEL, SN
中科院分区：
文献类型：
--
作者：
BARBER, SA;FULTZ, MJ;VOGEL, SN
巨噬细胞在脂多糖（LPS）刺激后分泌干扰素（IFN）以及其他细胞因子。干扰素调节因子（IRFs）包括一个DNA结合蛋白家族，其参与IFN和某些IFN诱导基因的转录调节。因此，我们的特点是基础和LPS诱导水平的IRF-1，IRF-2，和干扰素共有序列结合蛋白（ICSBP）的mRNA在LPS反应性巨噬细胞，并比较这些基因的表达在巨噬细胞，代表两个小鼠模型的LPS低反应性。在第一个模型中，C3 H/HeJ小鼠的LPS低反应表型由遗传决定，并定位于小鼠4号染色体上的LPS基因座。在第二种模型中，正常LPS-应答性巨噬细胞在先前暴露于LPS后获得瞬时LPS-低应答表型，这种现象被称为“内毒素耐受性”。使用逆转录PCR，我们检测到LPS应答（Lps（R））巨噬细胞中IRF-1 mRNA的基础水平比LPS低应答（Lps（R））巨噬细胞中的水平高约15倍。相反，LPS（d）巨噬细胞表达的IRF-2 mRNA基础水平比LPS（n）巨噬细胞高约18倍。LPS刺激导致IRF-1、IRF-2和ICSBP mRNA仅在LPS（n）巨噬细胞中呈剂量和时间依赖性蓄积。放线菌酮抑制LPS刺激的IRF-2和ICSBP mRNA的积累，但不抑制IRF-1 mRNA的积累，因此将IRF-1指定为立即早期的LPS诱导基因。最后，巨噬细胞呈现耐受内毒素表达升高，但非最大的mRNA水平的所有三个转录因子，不会再诱导后，与LPS的二次挑战。因此，IRP可能代表了对LPS的复杂反应中的另一个分子途径。
Macrophages secrete interferon (IFN), as well as other cytokines, following lipopolysaccharide (LPS) stimulation. The interferon regulatory factors (IRFs) comprise a family of DNA-binding proteins that have been implicated in the transcriptional regulation of IFN and certain IFN-inducible genes. We therefore characterized basal and LPS-inducible levels of IRF-1, IRF-2, and interferon consensus sequence binding protein (ICSBP) mRNA in LPS-responsive macrophages and compared the expression of these genes in macrophages that typify two murine models of LPS hyporesponsiveness. In the first model, the LPS-hyporesponsive phenotype of the C3H/HeJ mouse is genetically determined and maps to the Lps locus on mouse chromosome 4. In the second model, normally LPS-responsive macrophages acquire a transient LPS-hyporesponsive phenotype following a prior exposure to LPS, a phenomenon referred to as ''endotoxin tolerance.'' Using reverse transcription PCR, we detected basal levels of IRF-1 mRNA in LPS-responsive (Lps(R)) macrophages that were approximately 15 times higher than those found in LPS-hyporesponsive (Lps(R)) macrophages. Conversely, Lps(d) macrophages expressed basal levels of IRF-2 mRNA that were approximately 18 times higher than those expressed in Lps(n) macrophages. LPS stimulation resulted in a dose- and time-dependent accumulation of IRF-1, IRF-2, and ICSBP mRNA only in Lps(n) macrophages. Cycloheximide inhibited the accumulation of LPS stimulated IRF-2 and ICSBP mRNA, but not IRF-1 mRNA, thus designating IRF-1 an immediate-early, LPS-inducible gene. Finally, macrophages rendered tolerant to endotoxin expressed elevated but nonmaximal mRNA levels for all three transcription factors that are not reinduced upon secondary challenge with LPS. Thus, the IRPs may represent yet an additional molecular pathway in the complex response to LPS.