Abstract
Activation-induced cytidine deaminase (AID) plays critical roles in Ig class switch recombination and V(H) gene somatic hypermutation. We investigated the role of IL-4 in AID mRNA induction, the signaling transduction involved in IL-4-mediated AID induction, and the effect of CD45 on IL-4-dependent AID expression in human B cells. IL-4 was able to induce AID expression in human primary B cells and B cell lines, and IL-4-induced AID expression was further enhanced by CD40 signaling. IL-4-dependent AID induction was inhibited by a dominant-negative STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6 signaling pathway. Moreover, triggering of CD45 with anti-CD45 Abs can inhibit IL-4-induced AID expression, and this CD45-mediated AID inhibition correlated with the ability of anti-CD45 to suppress IL-4-activated JAK1, JAK3, and STAT6 phosphorylations. Thus, in humans, IL-4 alone is sufficient to drive AID expression, and CD40 signaling is required for optimal AID production; IL-4-induced AID expression is mediated via the JAK/STAT signaling pathway, and can be negatively regulated by the JAK phosphatase activity of CD45. This study indicates that the JAK phosphatase activity of CD45 can be induced by anti-CD45 Ab treatment, and this principle may find clinical application in modulation of JAK activation in immune-mediated diseases.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adjuvants, Immunologic / physiology
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Antibodies, Monoclonal / pharmacology
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B-Lymphocytes / enzymology
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B-Lymphocytes / immunology
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CD40 Antigens / physiology
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Cell Line
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Cells, Cultured
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Cytidine Deaminase / antagonists & inhibitors
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Cytidine Deaminase / biosynthesis*
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Down-Regulation / genetics
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Down-Regulation / immunology*
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Enzyme Induction / genetics
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Enzyme Induction / immunology
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Enzyme Inhibitors / pharmacology
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Enzyme Repression / genetics
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Enzyme Repression / immunology
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Humans
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Immunoglobulin Class Switching* / genetics
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Interleukin-4 / antagonists & inhibitors
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Interleukin-4 / physiology*
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Janus Kinase 1
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Janus Kinase 3
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Leukocyte Common Antigens / immunology
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Leukocyte Common Antigens / physiology*
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Lymphocyte Activation* / genetics
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Phosphorylation
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Protein Tyrosine Phosphatases / physiology*
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / physiology*
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STAT6 Transcription Factor
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Signal Transduction / genetics
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Signal Transduction / immunology
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
Substances
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Adjuvants, Immunologic
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Antibodies, Monoclonal
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CD40 Antigens
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Enzyme Inhibitors
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STAT6 Transcription Factor
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STAT6 protein, human
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Trans-Activators
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Interleukin-4
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Protein-Tyrosine Kinases
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JAK1 protein, human
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JAK3 protein, human
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Janus Kinase 1
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Janus Kinase 3
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Leukocyte Common Antigens
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Protein Tyrosine Phosphatases
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Cytidine Deaminase