| First Author | Mukherjee T | Year | 2017 |
| Journal | EMBO J | Volume | 36 |
| Issue | 23 | Pages | 3501-3516 |
| PubMed ID | 29061763 | Mgi Jnum | J:258322 |
| Mgi Id | MGI:6117981 | Doi | 10.15252/embj.201796919 |
| Citation | Mukherjee T, et al. (2017) A TNF-p100 pathway subverts noncanonical NF-kappaB signaling in inflamed secondary lymphoid organs. EMBO J 36(23):3501-3516 |
| abstractText | Lymphotoxin-beta receptor (LTbetaR) present on stromal cells engages the noncanonical NF-kappaB pathway to mediate RelB-dependent expressions of homeostatic chemokines, which direct steady-state ingress of naive lymphocytes to secondary lymphoid organs (SLOs). In this pathway, NIK promotes partial proteolysis of p100 into p52 that induces nuclear translocation of the RelB NF-kappaB heterodimers. Microbial infections often deplete homeostatic chemokines; it is thought that infection-inflicted destruction of stromal cells results in the downregulation of these chemokines. Whether inflammation per se also regulates these processes remains unclear. We show that TNF accumulated upon non-infectious immunization of mice similarly downregulates the expressions of these chemokines and consequently diminishes the ingress of naive lymphocytes in inflamed SLOs. Mechanistically, TNF inactivated NIK in LTbetaR-stimulated cells and induced the synthesis of Nfkb2 mRNA encoding p100; these together potently accumulated unprocessed p100, which attenuated the RelB activity as inhibitory IkappaBdelta. Finally, a lack of p100 alleviated these TNF-mediated inhibitions in inflamed SLOs of immunized Nfkb2(-/-) mice. In sum, we reveal that an inhibitory TNF-p100 pathway modulates the adaptive compartment during immune responses. |
