title: Epithelial Control of Gut-Associated Lymphoid Tissue Formation through p38α-Dependent Restraint of NF-κB Signaling.
abstract: 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.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;
authors.forename: Celia
authors.initials: C
authors.lastname: Caballero-Franco
authors.affiliation: 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;
authors.forename: Monica
authors.initials: M
authors.lastname: Guma
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;
authors.forename: Min-Kyung
authors.identifier: http://orcid.org/0000-0003-1492-7539
authors.initials: MK
authors.lastname: Choo
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Sano
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129; Department of Medicine, University of Arizona Cancer Center, Tucson, AZ 85724;
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0001-9838-9357
authors.initials: T
authors.lastname: Enzler
authors.affiliation: Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: Department of Pathology, Molecular Pathology Unit, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizoguchi
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129; jmpark@cbrc2.mgh.harvard.edu.
authors.forename: Jin Mo
authors.initials: JM
authors.lastname: Park
mesh_terms: D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression; D006965:Hyperplasia; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D064307:Microbiota / Q000276:immunology; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010581:Peyer's Patches / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D048308:Mitogen-Activated Protein Kinase 14