TNF receptor-associated factor 2-dependent canonical pathway is crucial for the development of Peyer's patches.
Activation of the noncanonical pathway through the interaction of lymphotoxin (LT)-alpha(1)beta(2) and LT-betaR is essential for the development of secondary lymphoid organs including lymph nodes (LN) and Peyer's patches (PP). Although TNFR-associated factor (TRAF) 2 and TRAF5 were identified as signal transducers for the LT-betaR, roles for TRAF2 and TRAF5 in the development of secondary lymphoid organs remain obscure. In this study, we show that PP but not mesenteric LN development is severely impaired in traf2(-/-) and traf2(-/-)traf5(-/-) mice. Development of VCAM-1(+) and ICAM-1(+) mesenchymal cells and expression of CXCL13, a crucial chemokine for the development of PP, are severely impaired in PP anlagen in the intestines of traf2(-/-) mice. Surprisingly, TNF-alpha stimulation potently up-regulates cxcl13 mRNA expression in wild-type murine embryonic fibroblasts, which is impaired in traf2(-/-) and relA(-/-) murine embryonic fibroblasts. Moreover, RelA is recruited to the promoter of cxcl13 gene upon TNF-alpha stimulation and PP development is impaired in TNFR type 1 (tnfr1)(-/-) mice. These results underscore a crucial role for the TNFR1-TRAF2-RelA-dependent canonical pathway in the development of PP through up-regulation of cxcl13 mRNA.
Piao
Jiang-Hu
JH
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Yoshida
Hisahiro
H
Yeh
Wen-Chen
WC
Doi
Takahiro
T
Xue
Xin
X
Yagita
Hideo
H
Okumura
Ko
K
Nakano
Hiroyasu
H
D000818:Animals; D054382:Chemokine CXCL13; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000276:immunology*; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology; D018507:Gene Expression Regulation, Developmental / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000276:immunology; D007421:Intestine, Small / Q000166:cytology / Q000196:embryology / Q000276:immunology; D008198:Lymph Nodes / Q000196:embryology / Q000276:immunology; D053361:Lymphotoxin alpha1, beta2 Heterotrimer / Q000276:immunology; D053259:Lymphotoxin beta Receptor / Q000276:immunology; D008648:Mesoderm / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010581:Peyer's Patches / Q000166:cytology / Q000196:embryology* / Q000276:immunology; D047992:TNF Receptor-Associated Factor 2 / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D048015:TNF Receptor-Associated Factor 5 / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism
D054382:Chemokine CXCL13; D019743:Chemokines, CXC; C486386:Cxcl13 protein, mouse; C505699:Ltbr protein, mouse; D053361:Lymphotoxin alpha1, beta2 Heterotrimer; D053259:Lymphotoxin beta Receptor; C498144:Rela protein, mouse; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1