Caballero-Franco Celia, Guma Monica, Choo Min-Kyung, Sano Yasuyo, Enzler Thomas, Karin Michael, Mizoguchi Atsushi, Park Jin Mo
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;
Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California, San Diego, La Jolla, CA 92093; Division of Rheumatology, Allergy, and Immunology, School of Medicine, University of California, San Diego, La Jolla, CA 92093;
J Immunol. 2016 Mar 1;196(5):2368-76. doi: 10.4049/jimmunol.1501724. Epub 2016 Jan 20.
The protein kinase p38α mediates cellular responses to environmental and endogenous cues that direct tissue homeostasis and immune responses. Studies of mice lacking p38α in several different cell types have demonstrated that p38α signaling is essential to maintaining the proliferation-differentiation balance in developing and steady-state tissues. The mechanisms underlying these roles involve cell-autonomous control of signaling and gene expression by p38α. In this study, we show that p38α regulates gut-associated lymphoid tissue (GALT) formation in a noncell-autonomous manner. From an investigation of mice with intestinal epithelial cell-specific deletion of the p38α gene, we find that p38α serves to limit NF-κB signaling and thereby attenuate GALT-promoting chemokine expression in the intestinal epithelium. Loss of this regulation results in GALT hyperplasia and, in some animals, mucosa-associated B cell lymphoma. These anomalies occur independently of luminal microbial stimuli and are most likely driven by direct epithelial-lymphoid interactions. Our study illustrates a novel p38α-dependent mechanism preventing excessive generation of epithelial-derived signals that drive lymphoid tissue overgrowth and malignancy.
蛋白激酶p38α介导细胞对指导组织稳态和免疫反应的环境及内源性信号的应答。对几种不同细胞类型中缺乏p38α的小鼠的研究表明，p38α信号对于维持发育中和稳态组织中的增殖-分化平衡至关重要。这些作用背后的机制涉及p38α对信号传导和基因表达的细胞自主控制。在本研究中，我们表明p38α以非细胞自主方式调节肠道相关淋巴组织（GALT）的形成。通过对肠道上皮细胞特异性缺失p38α基因的小鼠进行研究，我们发现p38α可限制NF-κB信号传导，从而减弱肠道上皮中促进GALT的趋化因子表达。这种调节的丧失会导致GALT增生，在某些动物中还会导致黏膜相关B细胞淋巴瘤。这些异常现象独立于腔内微生物刺激而发生，最有可能是由直接的上皮-淋巴细胞相互作用驱动的。我们的研究阐明了一种新的p38α依赖性机制，可防止驱动淋巴组织过度生长和恶变的上皮衍生信号过度产生。
