| First Author | Zhao X | Year | 2012 |
| Journal | PLoS One | Volume | 7 |
| Issue | 3 | Pages | e32811 |
| PubMed ID | 22427889 | Mgi Jnum | J:186919 |
| Mgi Id | MGI:5433782 | Doi | 10.1371/journal.pone.0032811 |
| Citation | Zhao X, et al. (2012) Nfkb1 inhibits LPS-induced IFN-beta and IL-12 p40 production in macrophages by distinct mechanisms. PLoS One 7(3):e32811 |
| abstractText | BACKGROUND: Nfkb1-deficient murine macrophages express higher levels of IFN-beta and IL-12 p40 following LPS stimulation than control macrophages, but the molecular basis for this phenomenon has not been completely defined. Nfkb1 encodes several gene products including the NF-kappaB subunit p50 and its precursor p105. p50 is derived from the N-terminal of 105, and p50 homodimers can exhibit suppressive activity when overexpressed. The C-terminal region of p105 is necessary for LPS-induced ERK activation and it has been suggested that ERK activity inhibits both IFN-beta and IL-12 p40 following LPS stimulation. However, the contributions of p50 and the C-terminal domain of p105 in regulating endogenous IFN-beta(Ifnb) and IL-12 p40 (Il12b) gene expression in macrophages following LPS stimulation have not been directly compared. METHODOLOGY/PRINCIPAL FINDINGS: We have used recombinant retroviruses to express p105, p50, and the C-terminal domain of p105 (p105DeltaN) in Nfkb1-deficient murine bone marrow-derived macrophages at near endogenous levels. We found that both p50 and p105DeltaN inhibited expression of Ifnb, and that inhibition of Ifnb by p105DeltaN depended on ERK activation, because a mutant of p105DeltaN (p105DeltaNS930A) that lacks a key serine necessary to support ERK activation failed to inhibit. In contrast, only p105DeltaN but not p50 inhibited Il12b expression. Surprisingly, p105DeltaNS930A retained inhibitory activity for Il12b, indicating that ERK activation was not necessary for inhibition. The differential effects of p105DeltaNS930A on Ifnb and Il12b expression inversely correlated with the function of one of its binding partners, c-Rel. This raised the possibility that p105DeltaNS930A influences gene expression by interfering with the function of c-Rel. CONCLUSIONS: These results demonstrate that Nfkb1 exhibits multiple gene-specific inhibitory functions following TLR stimulation of murine macrophages. |
