Delayed polarization of mononuclear phagocyte transcriptional program by type I interferon isoforms

被引:20
作者
Stroncek, DF [1 ]
Basil, C
Nagorsen, D
Deola, S
Aricó, E
Smith, K
Wang, E
Marincola, FM
Panelli, MC
机构
[1] NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA
[2] Univ Med Berlin, Med Klin 2, Charite, Berlin, Germany
关键词
D O I
10.1186/1479-5876-3-24
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Background: Interferon ( IFN)-alpha is considered a key modulator of immunopathological processes through a signature-specific activation of mononuclear phagocytes (MPs). This study utilized global transcript analysis to characterize the effects of the entire type I IFN family in comparison to a broad panel of other cytokines on MP previously exposed to Lipopolysaccharide ( LPS) stimulation in vitro. Results: Immature peripheral blood CD14+ MPs were stimulated with LPS and 1 hour later with 42 separate soluble factors including cytokines, chemokines, interleukins, growth factors and IFNs. Gene expression profiling of MPs was analyzed 4 and 9 hours after cytokine stimulation. Four hours after stimulation, the transcriptional analysis of MPs revealed two main classes of cytokines: one associated with the alternative and the other with the classical pathway of MP activation without a clear polarization of type I IFNs effects. In contrast, after 9 hours of stimulation most type I IFN isoforms induced a characteristic and unique transcriptional pattern separate from other cytokines. These "signature" IFNs included; IFN-beta, IFN-alpha 2b/alpha 2, IFN-alpha 1, IFN-alpha 2, IFN-alpha C, IFN-alpha J1, IFN-alpha H2, and INF-alpha 4B and induced the over-expression of 44 genes, all of which had known functional relationships with IFN such as myxovirus resistance (Mx)-1, Mx-2, and interferon-induced hepatitis C-associated microtubular aggregation protein. A second group of type I IFNs segregated separately and in closer association with the type II IFN-gamma. The phylogenetic relationship of amino acid sequences among type I IFNs did not explain their subclassification, although differences at positions 94 through 109 and 175 through 189 were present between the signature and other IFNs. Conclusion: Seven IFN-alpha isoforms and IFN-beta participate in the late phase polarization of MPs conditioned by LPS. This information broadens the previous view of the central role played by IFN-alpha in autoimmunity and tumor rejection by including and/ or excluding an array of related factors likely to be heterogeneously expressed by distinct sub-populations of individuals in sickness or in response to biological therapy.
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页数:21
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