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Ca 2+ ‐related signaling events influence TLR9‐induced IL‐10 secretion in human B cells
Author(s) -
Ziegler Saskia,
Gartner Katrin,
Scheuermann Uwe,
Zoeller Tanja,
Hantzschmann Julia,
Over Benjamin,
Foermer Sandra,
Heeg Klaus,
BekeredjianDing Isabelle
Publication year - 2014
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.201343994
Subject(s) - biology , secretion , tlr9 , microbiology and biotechnology , immunology , genetics , gene , endocrinology , gene expression , dna methylation
Suppressory B‐cell function controls immune responses and is mainly dependent on IL‐10 secretion. Pharmacological manipulation of B‐cell‐specific IL‐10 synthesis could, thus, be therapeutically useful in B‐cell chronic lymphocytic leukemia, transplantation, autoimmunity and sepsis. TLR are thought to play a protagonistic role in the formation of IL‐10‐secreting B cells. The aim of the study was to identify the molecular events selectively driving IL‐10 production in TLR9‐stimulated human B cells. Our data highlight the selectivity of calcineurin inhibitors in blocking TLR9‐induced B‐cell‐derived IL‐10 transcription and secretion, while IL‐6 transcription and release, B‐cell proliferation, and differentiation remain unaffected. Nevertheless, TLR9‐induced IL‐10 production was found to be independent of calcineurin phosphatase activity and was even negatively regulated by NFAT. In contrast to TLR9‐induced IL‐6, IL‐10 secretion was highly sensitive to targeting of spleen tyrosine kinase (syk) and Bruton's tyrosine kinase. Further analyses demonstrated increased phosphorylation of Ca 2+ /calmodulin kinase II (CaMKII) in TLR9‐stimulated B cells and selective reduction of TLR9‐induced secretion of IL‐10 upon treatment with CaMKII inhibitors, with negligible impact on IL‐6 levels. Altogether, our results identify calcineurin antagonists as selective inhibitors of IL‐10 transcription and syk/Bruton´s tyrosine kinase‐induced Ca 2+ /calmodulin‐ and CaMKII‐dependent signaling as a pathway regulating the release of TLR9‐induced B‐cell‐derived IL‐10.