Interferon‐α mediates suppression of C‐reactive protein: Explanation for muted C‐reactive protein response in lupus flares?

Objective C‐reactive protein (CRP) is synthesized by hepatocytes in response to interleukin‐6 (IL‐6) during inflammation. Despite raised IL‐6 levels and extensive systemic inflammation, serum CRP levels remain low during most viral infections and disease flares of systemic lupus erythematosus (SLE). Because both viral infections and SLE are characterized by high levels of interferon‐α (IFNα), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP. Methods The interference of all 12 IFNα subtypes with CRP promoter activity induced by IL‐6 and IL‐1β was studied in a CRP promoter– and luciferase reporter–transfected human hepatoma cell line, Hep‐G2. CRP secretion by primary human hepatocytes was analyzed by enzyme‐linked immunosorbent assay. Results CRP promoter activity was inhibited by all single IFNα subtypes, as well as by 2 different mixtures of biologically relevant IFNα subtypes. The most prominent effect was seen using a leukocyte‐produced mixture of IFNα (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFNα was confirmed in primary human hepatocytes. CRP promoter inhibition was dose dependent and mediated via the type I IFN receptor. Transferrin production and Hep‐G2 proliferation/viability were not affected by IFNα. Conclusion The current study demonstrates that IFNα is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up‐regulated IFNα and a muted CRP response during SLE disease flares. Given the fundamental role of both IFNα and CRP in the immune response, our results are of importance for understanding the pathogenesis of SLE and may also contribute to understanding the differences in the CRP response between viral and bacterial infections.