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.
Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland Laboratory of Applied Immunobiology, University of Zurich, 8006 Zurich, Switzerland.
J Exp Med. 2014 Jun 2;211(6):1257-70. doi: 10.1084/jem.20131917. Epub 2014 May 26.
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.
与磷酸化 p38 的丝裂原活化蛋白激酶 (MAPK) 级联不同，T 细胞受体 (TCR) 信号导致 Tyr-323 上的磷酸化 (pY323，替代途径)。使用表达 p38α 和 p38β 且 Tyr-323 发生 F 取代的小鼠，我们发现替代性而非 MAPK 级联激活的 p38 上调了转录因子 NFATc1 和 IRF4，它们是增殖和细胞因子产生所必需的。相反，用 UV 或渗透压休克激活 p38 通过磷酸化和 NFATc1 的细胞质保留减轻了 TCR 介导的激活。值得注意的是，UVB 处理人银屑病病变可减少皮肤浸润的 p38 pY323(+)T 细胞 IRF4 和 IL-17 的产生。因此，p38 激活的不同机制汇聚到 NFATc1 上，对 T 细胞免疫产生相反的影响，这可能是光疗对银屑病有益的基础。
Zotero 插件
