Interleukin‐10 (IL‐10) mediated suppression of IL‐12 production in RAW 264.7 cells also involves c‐rel transcription factor

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Abstract
Summary: Interleukin‐10 (IL‐10) is known to inhibit IL‐12 production in macrophages primarily at the transcriptional level with the involvement of p50 and p65 nuclear factor‐κB (NF‐κB). We demonstrate that the c‐rel transcription factor also plays a major role in IL‐10‐mediated IL‐12 suppression. Treatment of macrophages with recombinant IL‐10 inhibited nuclear c‐rel levels, whereas addition of neutralizing anti‐IL‐10 antibody up‐regulated both nuclear c‐rel levels and IL‐12 production by macrophages. Decreased nuclear c‐rel was associated with a reduction in phosphorylation of inhibitory kappa B alpha (IκBα) in the cytoplasm, indicating that IL‐10 prevents degradation of IκBα and the subsequent translocation of c‐rel into the nucleus. Treatment with leptomycin B, a known inhibitor of c‐rel at a concentration of 10 nm, when used with anti‐IL‐10 antibody, resulted in reduced expression of IL‐12. In a complementary experiment, in vitro transient expression of p65 NF‐κB could not rescue the inhibitory effect of IL‐10 on IL‐12 production, suggesting that NF‐κB alone was not sufficient to restore IL‐12 production during IL‐10 treatment. However, over‐expression of c‐rel resulted in IL‐12 restoration upon stimulation with lipopolysaccharide plus interferon‐γ during IL‐10 treatment. Our studies highlight the involvement of c‐rel in IL‐10‐mediated IL‐12 regulation.

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