The Rel subunit of NF-kappaB-like transcription factors is a positive and negative regulator of macrophage gene expression: distinct roles for Rel in different macrophage populations.

Abstract

The role of Rel in the monocyte/macrophage lineage was examined in mice with an inactivated c‐rel gene. Although the frequency of monocytic cells was normal in Rel−/− mice, we show that Rel serves distinct roles in regulating gene expression and immune effector function in different mature macrophage populations. Stimulated Rel−/− resident peritoneal macrophages produced higher than normal levels of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), granulocyte colony‐stimulating factor (G‐CSF) and interleukin‐6 (IL‐6), but tumour necrosis factor‐alpha (TNF‐alpha) production was not induced. Diminished cytotoxic activity exhibited by resident Rel−/− macrophages was consistent with reduced nitric oxide production resulting from impaired up‐regulation of inducible nitric oxide synthase expression. While a similar altered pattern of IL‐6 and TNF‐alpha expression was observed in stimulated Rel−/− peritoneal effusion macrophages, cytotoxic activity, nitric oxide, GM‐CSF and G‐CSF production by these cells was normal. The alternate regulation of certain genes in the two macrophage populations coincided with different patterns of nuclear Rel/NF‐kappaB complexes expressed in normal resident and elicited cells. Collectively, these results establish that Rel is a positive or negative regulator of transcription in macrophages and that Rel has distinct roles in different macrophage populations.

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…The reason why c-Rel-dependent regulation of the subunits that comprise IL-12 differs for particular APC is unclear, but it is tempting to speculate that it may be linked to cDC and macrophages serving as the critical sources of IL-12 in primary and sustained immune responses, respectively. Similar findings for the c-Rel-dependent cell-type-specific control of GM-CSF, inducible nitric oxide synthase and G-CSF have also been documented (Gerondakis et al, 1996;Grigoriadis et al, 1996). In the case of GM-CSF, whereas c-Rel is required for its transcription in T cells (Gerondakis et al, 1996), it functions as a repressor of GM-CSF transcription in resident peritoneal macrophages but is dispensable for GM-CSF production by elicited peritoneal macrophages .…”

Leishmania majorAmastigotes Induce p50/c-Rel NF-κΒ Transcription Factor in Human Macrophages: Involvement in Cytokine Synthesis

“…The increased susceptibility to L. major is correlated with a defect in macrophage function. Resident macrophages from c-Rel-deficient mice showed a marked reduction in NO production and parasite killing compared to the results obtained with macrophages from wild-type mice (18). Thus, our finding that L. major selectively induces p50/c-Rel in human monocytes is consistent with the results described above and further illustrates the ability of a given cell to use different components of the NF-B family under various physiological or pathological conditions to fine-tune the gene activation response to the stimulus.…”

“…Transcriptional activity of Leishmania-induced NF-〉 complexes. It was demonstrated previously that the c-Rel transcription factor can act as a positive or negative regulator of transcription in macrophages (18). The transactivation function of the parasite-induced NF-B dimers was investigated.…”

“…Using the specific NF-〉 inhibitor CAPE (33), we showed that NF-B is also involved in Leishmania amastigote-induced IL-10 and TNF-␣ production. Interestingly, macrophages from c-Rel Ϫ/Ϫ mice produce reduced levels of TNF-␣ in response to Leishmania infection (18). On the other hand, c-Rel-containing complexes play a significant role in the regulation of other cytokine genes in macrophages, especially the IL-12p40 gene (17,42), and a recent study showed that c-Rel is required for IL-12p40 production by macrophages in response to several microbial product-transducing activation signals through a TLR (28).…”

Genetic approaches in mice to understand Rel/NF-κB and IκB function: transgenics and knockouts

“…Consistent with this pattern of expression, c-Rel is essential for a variety of functions in hemopoietic cells, although it is dispensable for mouse embryonic development. Although normal numbers of hemopoietic cells in c-rel 7/7 mice indicate that c-Rel is not essential for the di erentiation of hemopoietic precursors, mature lymphocytes and macrophages exhibit a number of activation-associated defects associated with B-and T-cell proliferation, isotype switching and the production of various cytokines and immune modulatory molecules Grigoriadis et al, 1996;Grumont et al, 1998;KoÈ ntgen et al, 1995). Impaired c-rel 7/7 B-cell proliferation in response to range of individual mitogens is due to a cell-cycle block in G1 and elevated activation-induced apoptosis .…”