A role for Fli-1 in B cell proliferation: implications for SLE pathogenesis.
Transgenic overexpression of Fli-1 in normal mice leads to SLE-like disease and increased expression was reported in SLE-affected human and murine lymphocytes. Reducing Fli-1 expression in MRL/lpr mice decreased antibody production, proteinuria, renal pathology, and mortality. Compared to those with wild-type expression of Fli-1, we report here that proliferative responses of Fli-1-deficient naïve B cells to several mitogens were reduced in lupus-prone and control mice. Expression of mitogen receptors, including BCR, TLR4, and TLR9, was not significantly impacted in Fli-1-deficient naïve B cells. IL12a transcripts were upregulated and NFAT transcripts were downregulated in Fli-1-deficient MRL/lpr B cells. These results demonstrate that Fli-1 deficiency affects B cell proliferative responses to mitogens, independent of BCR and TLR expression. IL12a and NFAT, known to influence proliferation, were identified as potential mediators of this effect. This may be a mechanism by which overexpression of Fli-1 contributes to B cell hyperactivity and subsequent SLE pathogenesis.
Bradshaw
Sarah
S
Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA. gallant@musc.edu
Zheng
W Jim
WJ
Tsoi
Lam C
LC
Gilkeson
Gary
G
Zhang
Xian K
XK
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D015536:Down-Regulation; D015870:Gene Expression; D053765:Interleukin-12 Subunit p35 / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D050778:NFATC Transcription Factors / Q000276:immunology / Q000378:metabolism; D051789:Proto-Oncogene Protein c-fli-1 / Q000172:deficiency / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
C497426:Fli1 protein, mouse; C508859:Il12a protein, mouse; D053765:Interleukin-12 Subunit p35; D050778:NFATC Transcription Factors; D051789:Proto-Oncogene Protein c-fli-1; D011947:Receptors, Antigen, B-Cell; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9