CD40 and B-cell receptor signalling induce MAPK family members that can either induce or repress Bcl-6 expression

A Batlle, V Papadopoulou, AR Gomes, S Willimott… - Molecular …, 2009 - Elsevier
A Batlle, V Papadopoulou, AR Gomes, S Willimott, JV Melo, K Naresh, EWF Lam
Molecular immunology, 2009Elsevier
Bcl-6 is essential for germinal centre development and normal antibody responses, and has
major roles in controlling B-cell proliferation and differentiation. Bcl-6 expression is tightly
controlled, but neither the nature of all the regulatory signals nor their interactions are
known. Bcl-6 expression is induced in Bcr-Abl expressing lymphoid cell lines by the tyrosine
kinase inhibitor, imatinib. We show that p38 MAPK mediates induction of Bcl-6 following
inhibition of Bcr-Abl by imatinib. Next we analyze p38 function in a germinal centre B-cell …
Bcl-6 is essential for germinal centre development and normal antibody responses, and has major roles in controlling B-cell proliferation and differentiation. Bcl-6 expression is tightly controlled, but neither the nature of all the regulatory signals nor their interactions are known. Bcl-6 expression is induced in Bcr-Abl expressing lymphoid cell lines by the tyrosine kinase inhibitor, imatinib. We show that p38 MAPK mediates induction of Bcl-6 following inhibition of Bcr-Abl by imatinib. Next we analyze p38 function in a germinal centre B-cell line, Ramos. p38 is phosphorylated under basal conditions, and studies with p38 inhibitors show that it induces Bcl-6 expression. Membrane bound CD40 ligand activates p38 but also other MAPK pathways that strongly repress Bcl-6 and the overall effect is reduction in Bcl-6 expression. Surprisingly soluble CD40 ligand induces Bcl-6 by activating p38 without activating the repressive pathways. Hence different types of CD40 signalling are associated with varying effects on Bcl-6 expression. Transcription reporter assays demonstrate p38 responsive sequences at about 4.5kb from the transcription start site. Immunocytochemistry of tonsil sections show phosphorylated p38 in a minor population of germinal centre B-cells. We demonstrate for the first time that p38 induces Bcl-6 transcription, but increased protein expression occurs only when the strong pathways repressing Bcl-6 are not activated.
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