IL-17 activates the classical NF-κB signaling pathway to upregulate chemokine signal inhibitor molecules RGS16 and RGS13 in autoimmune B cells of BXD2 mice (99.49)

Abstract

Abstract We have previously reported that IL-17 upregulated the expression of rgs13 and rgs16 to attest the migration response of B cell to CXCL12. This specific effect of IL-17 on B cells is associated with the development of spontaneous germinal center in the spleens of autoimmune BXD2 mice. This study is to determine if NF-κB signaling is involved in IL-17 mediated upregulation of RGS proteins in B cells. Western blotting and confocal imaging analyses both showed that IL-17 stimulation of B cells from BXD2 mice resulted in rapid (5 min) activation of the classical NF-κB pathway which can be characterized by phosphorylation of p65 (P-p65) and translocation of P-p65 to the nuclei. Significantly higher level of activated P-p65 was found in BXD2 B cells than in B6 and BXD2-Il17r-/- B cells (>4.0-fold, p<0.01). Expression of the endogenous p50 subunit of NF-κB in BXD2 B cells was also higher than in B6 B cells (5.0-fold, p<0.01) but was surprisingly lower than in BXD2-Il17r-/- B cells (2.5-fold, p<0.01). The activated NF-κB pathway by IL-17 in B cells correlated with the upregulation of RGS16 and RGS13 in both protein and mRNA levels. Inhibition of P-p65 significantly down-regulated the expression of rgs genes (6.0-fold), and released the B cell migration arrest induced by IL-17 stimulation. These data suggest that IL-17 directly upregulates the expression of RGS through activating the classical NF-κB pathway in autoreactive BXD2 B cells.