UP-REGULATION OF MONOCYTIC IL-10 BY TUMOR-NECROSIS-FACTOR-ALPHA AND CAMP ELEVATING DRUGS

被引:296
|
作者
PLATZER, C
MEISEL, C
VOGT, K
PLATZER, M
VOLK, HD
机构
[1] INST MOLEC BIOTECHNOL, D-07745 JENA, GERMANY
[2] HUMBOLDT UNIV BERLIN, CHARITE, INST MED IMMUNOL, D-10098 BERLIN, GERMANY
关键词
CYTOKINES; IL-10; PROMOTER; ILOPROST; IMMUNOMODULATION; PENTOXIFYLLINE; SEPSIS;
D O I
10.1093/intimm/7.4.517
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
It is well established that endotoxin [lipopolysacharide (LPS)] induces pro-inflammatory cytokine production in monocytes, which is followed by secretion of the anti-inflammatory cytokine, IL-10. IL-10 down-regulates inflammatory response [tumor necrosis factor (TNF)-alpha, IL-1, IL-6, IL-8] as well as IL-10 synthesis itself. We wondered whether pro-inflammatory cytokines such as TNF-alpha may be involved in the regulation of human IL-10 synthesis. TNF-alpha induced de novo IL-10 mRNA expression in a dose-dependent manner but no IL-10 protein in human peripheral blood mononuclear cells. Furthermore, LPS-induced IL-10 gene and protein expression was significantly inhibited by neutralizing anti-TNF-alpha mAb. On the basis of these results, we conclude that TNF-alpha is involved in the up-regulation of its antagonist IL-10. Paradoxically, drugs that effectively inhibit expression of TNF-alpha via the elevation of intracellular cAMP level (iloprost, pentoxifylline, prostaglandin E(2) and N6,2-O-dibutyryl cAMP) augmented the endotoxin-induced IL-10 synthesis at both protein and mRNA levels. In order to provide a basis for the analysis of the transcriptional regulation of the human IL-10 gene, we isolated a fragment of the human IL-10 gene containing 1308 bp of the 5' non-coding sequence. It shows remarkable homology to the mouse IL-10 promoter in regions that have been associated with transcriptional regulation, including a cAMP responsive element which could explain the cAMP-mediated effects. The lack of a NF-kappa B-like binding site in the human sequence suggests a NF-kappa B-independent mechanism of TNF-alpha-induced IL-10 gene activation. In summary, our data demonstrate that TNF-alpha and cAMP elevating mediators, via induction of IL-10, are part of a negative feedback circuit that controls acute inflammatory response.
引用
收藏
页码:517 / 523
页数:7
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