RESUMO
TAK1 (MAP3K7) mediation of the IκB kinase (IKK) complex-nuclear factor-κB (NF-κB) pathway is crucial for the activation of immune response and to perpetuate inflammation. Although progress has been made to understand TAK1 function in the B-cell receptor (BCR) signaling, the physiological roles of TAK1 in B-cell development, particularly in the bone marrow (BM), remain elusive. Previous studies suggested that the IKK complex is required for the development of immunoglobulin light chain λ-positive B cells, but not for receptor editing. In contrast, NF-κB activity is suggested to be involved in the regulation of receptor editing. Thus, NF-κB signaling in early B-cell development is yet to be fully characterized. Therefore, we addressed the role of TAK1 in early B-cell development. TAK1-deficient mice showed significant reduction of BM Igλ-positive B-cell numbers without any alteration in the BCR editing. Furthermore, the expression of survival factor Bcl-2 was reduced in TAK1-deficient BM B cells as assessed by microarray and quantitative PCR analyses. Ex vivo over-expression of exogenous Bcl-2 enhanced the survival of TAK1-deficient Igλ-positive B cells. TAK1-IKK-NF-κB signaling contributes to the survival of λ-chain-positive B cells through NF-κB-dependent anti-apoptotic Bcl-2 expression.
Assuntos
Linfócitos B/citologia , Sobrevivência Celular , Cadeias lambda de Imunoglobulina/metabolismo , MAP Quinase Quinase Quinases/fisiologia , Animais , Apoptose/genética , Sobrevivência Celular/genética , Células Cultivadas , Expressão Gênica , Genes bcl-2 , Camundongos , NF-kappa B/metabolismoRESUMO
Scarcely anyone would dispute that donor-specific B cells and the Abs that they produce can cause rejection of transplants. Less clear and more controversial, however, is the possibility that donor-specific B cells and the Abs that they produce are one or more means by which transplants can be protected from injury. In this article, we review and discuss this possibility and consider how less well-known functions of B cells and Abs might impact on the design of therapeutics and the management of transplant recipients.