Smad3 and Smad4 mediate transforming growth factor-β1-induced IgA expression in murine B lymphocytes

초록

Transforming growth factor (TGF)-β1 is well established as a critical IgA isotype switching factor and Smad molecules have been reported to act as transducers and transcriptional factors in the expression of TGF-β1-targeted genes. We examined the involvement of Smad proteins in TGF-β1-induced IgA expression. First, we found that TGF-β1 significantly increases endogenous germ-line (GL) α transcripts by LPS-stimulated CH12.LX.4933 (μ+) B lymphoma cells. To investigate its signaling mechanisms, the lymphoma cell line was transfected with pFL3 that contains the TGF-β-responsive element of the GLα promoter, and stimulated with TGF-β1. Similar to endogenous GLα transcripts, TGF-β1 induces GLα promoter activity and overexpression of Smad3 markedly enhances the promoter activity. This activity is further augmented by contransfected Smad4. On the other hand, Smad7 substantially abrogates the synergistic effect of Smad3/4 on GLα promoter activity. In adidtion, overexpression of Smad3/4 enhances TGF-β1-induced endogenous GLα transcripts in normal spleen B cells. Finally, in the presence of TGF-β1, overexpression of Smad3/4 selectively increases both surface IgA expression and IgA production. The results from the present study indicate that Smad3, Smad4, and Smad7, at least in part, serve as mediators linking TGF-β1 to transcriptional regulation of IgA switching related gene and regulation of IgA class switching.

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