No abstract

The role for inhibitory Fc gamma receptors class IIb (FcgammaRIIb) in the onset, progression and severity of several animal models of autoimmune diseases is well established. By contrast, the pathogenic potential of FcgammaRIIb in human autoimmune diseases remains largely unknown. Here we report the identification of a polymorphism in the human FCGR2B promoter (dbSNP no. rs3219018) that is associated in homozygosity with systemic lupus erythematosus (SLE) phenotype in European-Americans (OR=11.1, P=0.003). Experimental evidence correlates the polymorphism (a G-C substitution at position -343 relative to the start of transcription) with altered FcgammaRIIb expression and function. The G-C substitution correlated with decreased transcription of the FCGR2B promoter, and resulted in decreased binding of the AP1 transcription complex to the mutant promoter sequence. The surface expression of FcgammaRIIb receptors was significantly reduced in activated B cells from (-343 C/C) SLE patients. These findings suggest that genetic defects may lead to deregulated expression of the FCGR2B gene in -343 C/C homozygous subjects, and may play a role in the pathogenesis of human SLE.

No abstract

Transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) are multifunctional peptides intimately involved in the process of extracellular matrix remodeling. We recently showed that TGF-beta stimulates the human alpha 2(I) collagen gene by increasing the affinity of an Sp1-containing transcriptional complex bound to an upstream sequence termed the TbRE (Inagaki, Y., Truter, S. and Ramirez, F. (1994) J. Biol. Chem. 269, 14828-14834). Here, we report that the TbRE-bound complex also mediates the inhibitory signal of TNF-alpha. Nuclear proteins from cells treated with TNF-alpha bind to the TbRE sequence substantially more strongly than those from untreated cells. Additionally, TNF-alpha increases binding of a second protein complex that recognizes the negatively cis-acting element located immediately next to the TbRE. Thus, we postulate that TNF-alpha counteracts the TGF-beta-elicited stimulation of collagen gene expression through overlapping nuclear signaling pathways. One modifies the TGF-beta-targeted transcriptional complex, probably by reducing its stimulatory effect on collagen transcription. The other acts on the binding of the adjacent factor, presumably by increasing its effectiveness in repressing the activity of the collagen promoter. The convergence of the TGF-beta and TNF-alpha pathways on the same sequence of the alpha 2(I) collagen promoter is yet another example of combinatorial gene regulation achieved through composite response elements.