SCID mice reconstituted with XBP1−/− B cells fail to produce antibodies against polyoma virus and succumb at higher rate than control recipients. Enforced expression of XBP-1 in BCL1-3B3 cells, a B cell line, drive these cells towards plasma cell differentiation, and intense signals for XBP-1 transcripts were found in plasma cells from the sinovium from two patients with rheumatoid arthritis. These data demonstrate an essential and sufficient role for XBP-1 in directing plasma cell differentiation [85]. Consistent with this idea, activation of the UPR pathway was observed

during differentiation of antibody secreting B cells [87]. PARP inhibitor The CH12 murine B cell lymphoma was used as a model for plasma cell differentiation as they become IgM secreting cells in response to LPS. Treatment of CH12 cells with LPS elevated XBP-1 transcripts and induced the production of chaperones BiP and GRP94 before the translation of Ig chains occurred. Still, the highest levels of transcripts and chaperones were observed when intracellular Ig chains were also elevated. The increase in Igμ, Igκ, BiP, and GRP94 transcripts and proteins correlated with the induction of XBP-1 expression and ATF6 cleavage, MEK inhibitor but not CHOP induction. On the other hand, the treatment of those cells with tunicamycin robustly induced UPR targets and CHOP. These data suggest that other signals rather than unfolded/misfolded

Ig chains activate, at least in part, the UPR pathway [87]. In accordance with these data, the induction of XBP-1 mRNA in murine B lymphocytes was strongly increased in the presence of IL-4 in a protein synthesis-independent manner [53]. In addition, GRP78 and CHOP transcripts were up regulated after IL-4 treatment, suggesting

that UPR target genes are regulated by IL-4. Nevertheless, the splicing of XBP-1 mRNA by IRE1α depended on Ig synthesis. In addition, XBP-1 seemed to be required for Ig secretion by plasma cells: forced expression of XBP-1s enhanced IgM secretion in activated BCL1 cells (mature B cell lineage), and XBP-1s expression GBA3 restored IgM and IgG2b production in XBP1-deficient B cells. These findings support the requisite of UPR activation for plasma cell function [53]. In contrast with these findings [87], another study [88] employed I.29 μ+ lymphoma cell line treated with LPS as a model for plasma cell differentiation. XBP-1 was found in high amounts only when increased IgM synthesis was detected in day 3 and 4 post-stimulation. These differences could be explained by the different readout between the studies: one measured XBP-1 transcripts [87], while the other looked for the protein [88]. Microarray gene expression analysis was used to identify genes related to the secretory pathway (ER protein folding, protein glycosylation, vesicle trafficking) and cell differentiation whose expression relied on XBP-1.