Abstract
Unlike the MAP kinase (MAPK) cascade that phosphorylates p38 on the activation loop, T cell receptor (TCR) signaling results in phosphorylation on Tyr-323 (pY323, alternative pathway). Using mice expressing p38α and p38β with Y323F substitutions, we show that alternatively but not MAPK cascade-activated p38 up-regulates the transcription factors NFATc1 and IRF4, which are required for proliferation and cytokine production. Conversely, activation of p38 with UV or osmotic shock mitigated TCR-mediated activation by phosphorylation and cytoplasmic retention of NFATc1. Notably, UVB treatment of human psoriatic lesions reduced skin-infiltrating p38 pY323(+) T cell IRF4 and IL-17 production. Thus, distinct mechanisms of p38 activation converge on NFATc1 with opposing effects on T cell immunity, which may underlie the beneficial effect of phototherapy on psoriasis.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Enzyme Activation
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Female
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Gene Knock-In Techniques
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Humans
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Immunoblotting
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Interferon Regulatory Factors / genetics
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Interferon Regulatory Factors / immunology
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Interferon Regulatory Factors / metabolism
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Interleukin-17 / immunology
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Interleukin-17 / metabolism
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Isoenzymes / genetics
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Isoenzymes / immunology
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Isoenzymes / metabolism
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Lymphocyte Activation / immunology
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Lymphocyte Activation / radiation effects
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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NFATC Transcription Factors / genetics
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NFATC Transcription Factors / immunology
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NFATC Transcription Factors / metabolism
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Psoriasis / immunology
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Psoriasis / metabolism
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Psoriasis / radiotherapy
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Skin / immunology
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Skin / metabolism
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Skin / radiation effects
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism*
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Th17 Cells / immunology
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Th17 Cells / metabolism
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Tyrosine / metabolism
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Ultraviolet Rays
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Up-Regulation
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Interferon Regulatory Factors
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Interleukin-17
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Isoenzymes
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NFATC Transcription Factors
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Nfatc1 protein, mouse
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Receptors, Antigen, T-Cell
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interferon regulatory factor-4
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Tyrosine
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p38 Mitogen-Activated Protein Kinases