期刊
JOURNAL OF IMMUNOLOGY
卷 192, 期 7, 页码 3121-3132出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1302351
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资金
- National Institutes of Health [R01AI083453, P50GM]
- National Institutes of Health/National Cancer Institute [T32 CA009523]
- National Science Foundation Graduate Research Fellowship Program
The transcription factor NF-kappa B is a regulator of inflammatory and adaptive immune responses, yet only IkB alpha was shown to limit NF-kappa B activation and inflammatory responses. We investigated another negative feedback regulator, I kappa B epsilon, in the regulation of B cell proliferation and survival. Loss of I kappa B epsilon resulted in increased B cell proliferation and survival in response to both antigenic and innate stimulation. NF-kappa B activity was elevated during late-phase activation, but the dimer composition was stimulus specific. In response to IgM, cRel dimers were elevated in I kappa B epsilon-deficient cells, yet in response to LPS, RelA dimers also were elevated. The corresponding dimer-specific sequences were found in the promoters of hyperactivated genes. Using a mathematical model of the NF-kappa B-signaling system in B cells, we demonstrated that kinetic considerations of I kappa B kinase-signaling input and I kappa B epsilon s interactions with RelA-and cRel-specific dimers could account for this stimulus specificity. cRel is known to be the key regulator of B cell expansion. We found that the RelA-specific phenotype in LPS-stimulated cells was physiologically relevant: unbiased transcriptome profiling revealed that the inflammatory cytokine IL-6 was hyperactivated in I kappa B epsilon(-/-) B cells. When IL-6R was blocked, LPS-responsive I kappa B epsilon(-/-) B cell proliferation was reduced to near wild-type levels. Our results provide novel evidence for a critical role for immune-response functions of I kappa B epsilon in B cells; it regulates proliferative capacity via at least two mechanisms involving cRel- and RelA-containing NF-kappa B dimers. This study illustrates the importance of kinetic considerations in understanding the functional specificity of negative-feedback regulators.
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