TNFR and LTbetaR agonists induce follicle-associated epithelium and M cell specific genes in rat and human intestinal epithelial cells.
M cells assist mucosal immune surveillance by transcytosis of particles to underlying lymphoid tissue, but the mechanisms of M cell differentiation are poorly understood. To develop a better defined cell culture model of M cell differentiation, we treated human (Caco-2BBe) and rat (IEC-6) intestinal epithelial cell lines with lymphotoxin beta receptor (LTbetaR) and TNF receptor (TNFR) agonists. Treated cells were studied for regulation of genes associated with M cell and follicle-associated epithelium (FAE). We found that LTbetaR and TNFR agonists induce transcription of FAE-specific genes (Ccl20 and Lamb3) in Caco2-BBe cells and IEC-6 cells as well as rodent M cell specific genes such as Sgne-1/Scg5, Cldn4, and Gp2. The cytokines have distinct but complementary effects; TNFR agonists mainly induced FAE-specific genes, while the LTbetaR agonist induced M cell specific genes. The combination of cytokines showed additive induction of the FAE-associated Ccl20, Lamb3 and a surprising induction of CD137/Tnfrsf9. On the other hand TNF agonists appeared to suppress expression of some LTbetaR-induced genes. Functionally, cytokine treatment led to the reorganization of microvilli and Claudin-4 redistribution. These studies suggest complex interactions between these cytokines in the context of either inflammation or tissue differentiation.
Wang
Jing
J
Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA.
Lopez-Fraga
Marta
M
Rynko
Abby
A
Lo
David D
DD
D000818:Animals; D017304:Annexin A5 / Q000235:genetics; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D018938:Caco-2 Cells; D015815:Cell Adhesion Molecules / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D054418:Chemokine CCL20 / Q000235:genetics; D062506:Claudin-4; D016207:Cytokines / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D058851:GPI-Linked Proteins; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology*; D053259:Lymphotoxin beta Receptor / Q000819:agonists* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008871:Microvilli / Q000187:drug effects; D051859:Neuroendocrine Secretory Protein 7B2 / Q000235:genetics; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists*; D013211:Staphylococcus aureus / Q000276:immunology; D051841:Transcription Factor RelB / Q000235:genetics; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*; D000097794:Kalinin
D017304:Annexin A5; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D054418:Chemokine CCL20; D062506:Claudin-4; D016207:Cytokines; D058851:GPI-Linked Proteins; D053259:Lymphotoxin beta Receptor; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D051859:Neuroendocrine Secretory Protein 7B2; D018124:Receptors, Tumor Necrosis Factor; D051841:Transcription Factor RelB; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D000097794:Kalinin; C568157:CLDN4 protein, human; C066161:Gp2 protein, rat; C491877:Pglyrp1 protein, rat; C497680:Scg5 protein, rat