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Background    Nfkb1 -deficient murine macrophages express higher levels of IFN-β 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-κB 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-β and IL-12 p40 following LPS stimulation. However, the contributions of p50 and the C-terminal domain of p105 in regulating endogenous IFN-β( 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 (p105ΔN) in  Nfkb1 -deficient murine bone marrow-derived macrophages at near endogenous levels. We found that both p50 and p105ΔN inhibited expression of  Ifnb , and that inhibition of  Ifnb  by p105ΔN depended on ERK activation, because a mutant of p105ΔN (p105ΔNS930A) that lacks a key serine necessary to support ERK activation failed to inhibit. In contrast, only p105ΔN but not p50 inhibited  Il12b  expression. Surprisingly, p105ΔNS930A retained inhibitory activity for  Il12b , indicating that ERK activation was not necessary for inhibition. The differential effects of p105ΔNS930A on  Ifnb  and  Il12b  expression inversely correlated with the function of one of its binding partners, c-Rel. This raised the possibility that p105ΔNS930A 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.

Nfkb1 Inhibits LPS-Induced IFN-β and IL-12 p40 Production in Macrophages by Distinct Mechanisms