NFkappaB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells
We examined the role of NFkappaB1 in the homeostasis and function of peripheral follicular (Fo) B cells. Aging mice lacking NFkappaB1 (Nfkappab1(-/-)) develop lymphoproliferative and multiorgan autoimmune disease attributed in large part to the deregulated activity of Nfkappab1(-/-)Fo B cells that produce excessive levels of the proinflammatory cytokine interleukin 6 (IL-6). Despite enhanced germinal center (GC) B cell differentiation, the formation of GC structures was severely disrupted in the Nfkappab1(-/-)mice. Bone marrow chimeric mice revealed that the Fo B cell-intrinsic loss of NFkappaB1 led to the spontaneous generation of GC B cells. This was primarily the result of an increase in IL-6 levels, which promotes the differentiation of Fo helper CD4(+)T cells and acts in an autocrine manner to reduce antigen receptor and toll-like receptor activation thresholds in a population of proliferating IgM(+)Nfkappab1(-/-)Fo B cells. We demonstrate that p50-NFkappaB1 represses Il-6 transcription in Fo B cells, with the loss of NFkappaB1 also resulting in the uncontrolled RELA-driven transcription of Il-6.Collectively, our findings identify a previously unrecognized role for NFkappaB1 in preventing multiorgan autoimmunity through its negative regulation of Il-6 gene expression in Fo B cells.
|ISBN||0022-1007 (Print) 0022-1007 (Linking)|
|Authors||de Valle, E.; Grigoriadis, G.; O'Reilly, L. A.; Willis, S. N.; Maxwell, M. J.; Corcoran, L. M.; Tsantikos, E.; Cornish, J. K.; Fairfax, K. A.; Vasanthakumar, A.; Febbraio, M. A.; Hibbs, M. L.; Pellegrini, M.; Banerjee, A.; Hodgkin, P. D.; Kallies, A.; Mackay, F.; Strasser, A.; Gerondakis, S.; Gugasyan, R.;|
|Publisher Name||JOURNAL OF EXPERIMENTAL MEDICINE|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/27022143|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/13591|