The present study next suggests that CD40 engagement, in the abse

The present study next suggests that CD40 engagement, in the absence of other (known) stimuli, is sufficient to effectively induce IgA switching in human B cells, in a NF-κB-dependent manner [46]. IL-10 is the pleiotropic regulator of the immune system toward infection. It plays a central role in B cell proliferation, survival, isotype switching and differentiation [47]. Our results check details indeed confirm the involvement of IL-10 in IgA production; however, as IL-10 induced STAT3 and CD40L NF-κB, we next attempted to elucidate their respective influences on IgA production. The STAT3 protein is a STAT family member with diverse biological functions, including cell growth,

cell survival, embryo development and cell motility [30,48,49]. STAT3 was shown to play a critical

role in mouse B cell development, particularly in the thymodependent terminal differentiation of B cells into IgG plasma cells [50]. STAT3 was also identified recently as a major player in hyper-IgE syndrome [51]. Diehl et al. used human B cells to show that the inducible activation of STAT3 triggers blimp1 gene expression and promotes plasma cell differentiation and Ig production [52]. STAT3 and/or IL-10 mutations have been shown to be involved Palbociclib clinical trial in inflammatory bowel disease, Crohn’s disease or ulcerative colitis, impairing the signalling pathways [53]. STAT3 plays a major role in the IL-23/Th17 pathway, maintaining intestinal immune homeostasis [54]. However, it is becoming increasingly clear that IL-10 signalling appears to play a central role in inflammatory bowel disease pathogenesis, with germline variants associated with ulcerative colitis and Crohn’s disease [55,56]. Here, we present evidence that the STAT3 pathway is also critical for either Ig (or more particularly IgA) production by human B cells or for export of IgA onto human B cells. Fan et al. showed that B cell stimulation by Ig triggering leads to STAT3 activation that depends on the combined effects of IL-6 and IL-10, whereas anti-Ig or pharmacological stimulation with phorbol

myristate acetate (PMA)/ionomycin leads to STAT3 activation that depends primarily on IL-10 [57]. IL-10 also mediates the differentiation of germinal centre B cells into memory and plasma cells PAK5 [58] and induces Janus kinase (JAK) proteins via the phosphorylation of STAT3 [59]. Here, we report that IL-10 by itself can lead to significant AID transcription and IgA production and that a combination of sCD40L and IL-10 induced comparable levels of IgA to those induced by IL-10 alone. Consequently, we propose that IgA synthesis by (in vitro) differentiated B cells is more dependent on the STAT3 pathway than on the NF-κB pathway. However, in the absence of IL-10 or when the STAT3 pathway is blocked, some IgA can still be produced by B cells, albeit in smaller quantities.

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