Abstract
Major histocompatibility complex class I-related chain (MICA) is a cell stress-regulated molecule recognized by cytotoxic cells expressing the NKG2D molecule. MICA can be induced on T cells after CD3 or CD28 engagement. Here, we investigated the intracellular pathways leading to activation-induced expression of MICA. The Src kinase inhibitor PP1 inhibited up-regulated expression of MICA on anti-CD3-stimulated T cells. Downstream signaling routes involved mitogen-activated protein kinase (MAPK) kinase (MEK)1/extracellular signal-regulated kinase (ERK), p38 MAPK, and calcineurin, as MICA expression was prevented by U0126, SB202190, cyclosporin A, and FK506. Also, Lck and Fyn as well as MEK1/ERK and p38 MAPK were found to regulate MICA expression in anti-CD28/phorbol 12-myristate 13-acetate-stimulated T cells. Expression of MICA on activated T cells involved interleukin-2-dependent signaling routes triggered by Janus tyrosine kinases/signal transducer and activators of transcription and p70(S)(6) kinase, as it could be inhibited by AG490 and rapamycin. This is the first demonstration of the intracellular pathways involved in activation-induced expression of MICA, which may reveal potential targets for immune intervention to modulate MICA expression in pathological disorders.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Calcineurin / metabolism
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Cells, Cultured
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Enzyme Inhibitors / pharmacology
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Histocompatibility Antigens Class I / biosynthesis*
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Humans
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Interleukin-2 / physiology
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Lymphocyte Activation
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / physiology
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MAP Kinase Kinase 1
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MAP Kinase Signaling System*
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-fyn
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Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors
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Ribosomal Protein S6 Kinases, 70-kDa / physiology
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Signal Transduction
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T-Lymphocytes / enzymology*
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T-Lymphocytes / immunology*
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Up-Regulation*
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p38 Mitogen-Activated Protein Kinases
Substances
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Enzyme Inhibitors
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Histocompatibility Antigens Class I
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Interleukin-2
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MHC class I-related chain A
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Proto-Oncogene Proteins
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FYN protein, human
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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Proto-Oncogene Proteins c-fyn
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Protein Serine-Threonine Kinases
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Ribosomal Protein S6 Kinases, 70-kDa
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases
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Calcineurin