Suppression of IL-12 Transcription in Macrophages Following Fcγ Receptor Ligation

Abstract

Ligating FcγR on macrophages results in suppression of IL-12 production. We show that FcγR ligation selectively down-regulates IL-12 p40 and p35 gene expression at the level of transcription. The region responsive to this inhibition maps to the Ets site of the p40 promoter. PU.1, IFN consensus sequence binding protein, and c-Rel form a complex on this element upon macrophage activation. Receptor ligation abolishes the binding of this PU.1-containing activation complex, and abrogates p40 transcription. A dominant-negative construct of PU.1 diminishes IL-12 p40 promoter activity and endogenous IL-12 p40 protein secretion. Thus, the specificity of IL-12 down-regulation following receptor ligation lies in the inhibition of binding of a PU.1-containing complex to the Ets site of the IL-12 promoter. These findings provide evidence demonstrating for the first time the importance of PU.1 in the transcriptional regulation of IL-12 gene expression.

Cutting Edge: Biasing Immune Responses by Directing Antigen to Macrophage Fcγ Receptors

“…4A, left panel). This observation is consistent with our previous reports of cytokine production by macrophages stimulated by a variety of microbial products (10,11). Parallel wells of macrophages were stimulated in the same way but were given IgG-OVA as the Ag instead of OVA alone.…”

“…Breeding pairs of IL-10 Ϫ/Ϫ mice were kindly provided by D. Rennick (DNAX, Palo Alto, CA). Macrophages were prepared from the bone marrow progenitors as previously described (10). CD4 ϩ cells were prepared from the spleens of DO11.10 mice by immunomagnetic negative depletion (Polysciences, Warrington, PA).…”

Increased expression of Fcγ receptors II and III on macrophages of rheumatoid arthritis patients results in higher production of tumor necrosis factor α and matrix metalloproteinase

“…However, one would then expect that other cytokines, such as TNF␣, would also be down-regulated. A more plausible explanation may be that IC stimulation causes inhibition of IL-12 production by macrophages, as was previously reported by Sutterwala et al and Grazia Cappiello et al (58,59). Unfortunately, IL-12 production could not be detected in the culture supernatants, either in the presence or absence of HAGG stimulation (data not shown), leaving us unable to show this inhibition of IL-12 production in our in vitro system.…”

Activation of the Murine Interleukin-12 p40 Promoter by Functional Interactions between NFAT and ICSBP

“…The regulation of NFAT5 is calcium flux-independent (43). It is generally believed that Ca 2ϩ flux induced by Fc␥ receptors cause inhibition of IL-12 production in response to LPS (44), or IFN-␥ and LPS (45). Whether LPS can trigger Ca 2ϩ mobilization is still controversial (46,47).…”