title: Complexes between nuclear factor-κB p65 and signal transducer and activator of transcription 3 are key actors in inducing activation-induced cytidine deaminase expression and immunoglobulin A production in CD40L plus interleukin-10-treated human blood B cells.
abstract: The signal transducer and activator of transcription 3 (STAT3) transcription factor pathway plays an important role in many biological phenomena. STAT3 transcription is triggered by cytokine-associated signals. Here, we use isolated human B cells to analyse the role of STAT3 in interleukin (IL)-10 induced terminal B cell differentiation and in immunoglobulin (Ig)A production as a characteristic readout of IL-10 signalling. We identified optimal conditions for inducing in-vitro IgA production by purified blood naive B cells using IL-10 and soluble CD40L. We show that soluble CD40L consistently induces the phosphorylation of nuclear factor (NF)-κB p65 but not of STAT3, while IL-10 induces the phosphorylation of STAT3 but not of NF-κB p65. Interestingly, while soluble CD40L and IL-10 were synergistic in driving the terminal maturation of B cells into IgA-producing plasma cells, they did not co-operate earlier in the pathway with regard to the transcription factors NF-κB p65 or STAT3. Blocking either NF-κB p65 or STAT3 profoundly altered the production of IgA and mRNA for activation-induced cytidine deaminase (AID), an enzyme strictly necessary for Ig heavy chain recombination. Finally, the STAT3 pathway was directly activated by IL-10, while IL-6, the main cytokine otherwise known for activating the STAT3 pathway, did not appear to be involved in IL-10-induced-STAT3 activation. Our results suggest that STAT3 and NF-κB pathways co-operate in IgA production, with soluble CD40L rapidly activating the NF-κB pathway, probably rendering STAT3 probably more reactive to IL-10 signalling. This novel role for STAT3 in B cell development reveals a potential therapeutic or vaccine target for eliciting IgA humoral responses at mucosal interfaces.
authors: EFS Auvergne-Loire, Saint-Etienne, France.
authors: S
authors: S
authors: Lafarge
authors: H
authors: H
authors: Hamzeh-Cognasse
authors: Y
authors: Y
authors: Richard
authors: B
authors: B
authors: Pozzetto
authors: M
authors: M
authors: Cogné
authors: F
authors: F
authors: Cognasse
authors: O
authors: O
authors: Garraud
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D023201:CD40 Ligand / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000096:biosynthesis*; D004790:Enzyme Induction; D006801:Humans; D007070:Immunoglobulin A / Q000096:biosynthesis* / Q000276:immunology; D016753:Interleukin-10 / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D007070:Immunoglobulin A; D015850:Interleukin-6; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051996:Transcription Factor RelA; D016753:Interleukin-10; D023201:CD40 Ligand; D003564:Cytidine Deaminase