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* Department of General Surgery, Wake Forest University School of Medicine, Winston-Salem, NC 27157; and
Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157
Using a THP-1 human promonocyte model of endotoxin tolerance that simulates the sepsis leukocyte phenotype, we previously showed that tolerant cells remain responsive to LPS endotoxin with degradation of I
B in the cytosol and nuclear translocation and accumulation of p50 and p65 NF-B transcription factors. Despite this, endotoxin-inducible NF-B-dependent innate immunity genes, like IL-1
, remained transcriptionally unresponsive in the tolerant phenotype, similar to the endotoxin tolerance observed in sepsis patients. In this study, we examined this paradox and found that RelB, another member of the NF-B family, is induced during the establishment of tolerance. RelB expression correlated with IL-1 repression, and sepsis patients showed increased RelB when compared with normal controls. Transient expression of RelB inhibited IL-1 in endotoxin-responsive cells. In the inverse experiment, small inhibitory RNAs decreased RelB expression in tolerant cells and restored endotoxin induction of IL-1. When we examined tolerant cell extracts, we found transcriptionally inactive NF-B p65/RelB heterodimers. Taken together, our findings demonstrate that RelB can repress proinflammatory gene expression, and suggest that RelB expression in sepsis patient blood leukocytes may play a role in the endotoxin-tolerant phenotype.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant AI-09169 (to C.E.M.) and MO1-RR007122 to the Wake Forest University Medical Center General Clinical Research Center.
2 Address correspondence and reprint requests to Dr. Barbara K. Yoza, Wake Forest University School of Medicine, Department of Surgery, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail address: byoza{at}wfubmc.edu
3 Abbreviations used in this paper: IRAK, IL-1R-associated kinase; ChIP, chromatin immunoprecipitation; DC, dendritic cell; PMN, polymorphonuclear blood leukocyte; siRNA, small interfering RNA.
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