| First Author | Alves BN | Year | 2014 |
| Journal | J Immunol | Volume | 192 |
| Issue | 7 | Pages | 3121-32 |
| PubMed ID | 24591377 | Mgi Jnum | J:209870 |
| Mgi Id | MGI:5568858 | Doi | 10.4049/jimmunol.1302351 |
| Citation | Alves BN, et al. (2014) IkappaBepsilon is a key regulator of B cell expansion by providing negative feedback on cRel and RelA in a stimulus-specific manner. J Immunol 192(7):3121-32 |
| abstractText | The transcription factor NF-kappaB is a regulator of inflammatory and adaptive immune responses, yet only IkappaBalpha was shown to limit NF-kappaB activation and inflammatory responses. We investigated another negative feedback regulator, IkappaBepsilon, in the regulation of B cell proliferation and survival. Loss of IkappaBepsilon resulted in increased B cell proliferation and survival in response to both antigenic and innate stimulation. NF-kappaB activity was elevated during late-phase activation, but the dimer composition was stimulus specific. In response to IgM, cRel dimers were elevated in IkappaBepsilon-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-kappaB-signaling system in B cells, we demonstrated that kinetic considerations of IkappaB kinase-signaling input and IkappaBepsilon'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 IkappaBepsilon(-/-) B cells. When IL-6R was blocked, LPS-responsive IkappaBepsilon(-/-) B cell proliferation was reduced to near wild-type levels. Our results provide novel evidence for a critical role for immune-response functions of IkappaBepsilon in B cells; it regulates proliferative capacity via at least two mechanisms involving cRel- and RelA-containing NF-kappaB dimers. This study illustrates the importance of kinetic considerations in understanding the functional specificity of negative-feedback regulators. |
