title: Counter-regulation of T cell effector function by differentially activated p38.
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.
authors.affiliation: Laboratory of Immune Cell Biology, Center for Cancer Research; Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Muhammad S
authors.initials: MS
authors.lastname: Alam
authors.affiliation: Laboratory of Immune Cell Biology, Center for Cancer Research; Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Gaida
authors.affiliation: Laboratory of Immune Cell Biology, Center for Cancer Research; Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Youichi
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland Laboratory of Applied Immunobiology, University of Zurich, 8006 Zurich, Switzerland.
authors.forename: Antonios G A
authors.initials: AG
authors.lastname: Kolios
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.affiliation: Laboratory of Immune Cell Biology, Center for Cancer Research; Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 jda@pop.nci.nih.gov.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashwell
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D015151:Immunoblotting; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011565:Psoriasis / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D014466:Ultraviolet Rays; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D020381:Interleukin-17; D007527:Isoenzymes; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D048051:p38 Mitogen-Activated Protein Kinases; D000099218:Interferon Regulatory Factor-4; C494005:Nfatc1 protein, mouse