Interleukin-1β stimulates acute phase response and C-reactive protein synthesis by inducing an NFκB- and C/EBPβ-dependent autocrine interleukin-6 loop

Cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) are involved in acute phase response (APR). C-reactive protein (CRP), the prototype acute phase protein, may represent an important component in the pathogenesis of arteriosclerosis and may also be a target for drug development. Inhibition of CRP synthesis is one potential strategy. Understanding CRP synthesis, however, is a prerequirement for the development of CRP-inhibitors. From studies in hepatoma cell lines, IL-1β and IL-6 were considered as equal inductors of APR and CRP.We investigated IL-1β- and IL-6-effects on primary human hepatocytes (PHH) and Hep3B-cells. Kupffer cell contamination in PHH preparations was <3%. In PHH, several APP like CRP, haptoglobin (HP), lipopolysaccharide-binding protein (LBP) or hepcidin (HAMP) were regulated similarly by IL-1β and IL-6, though signal transduction pathways of these cytokines are different. In Hep3B-cells, APP were regulated exclusively by IL-6. IL-1β induced IL-6-synthesis in PHH but not in Hep3B-cells. C/EBPβ-overexpression in Hep3B-cells reconstituted IL-1β-mediated IL-6/CRP inducibility. In PHH and in C/EBPβ-overexpressing Hep3B-cells, neutralizing anti-IL-6-antibodies blocked IL-1β-mediated APR. Inhibition of protein synthesis and NFκB-signalling blocked IL-1β- but not IL-6-mediated CRP-expression in PHH, whereas Janus-Kinase-1-inhibition blocked IL-1β- and IL-6-mediated APR.IL-1β induces APR in PHH via an NFκB- and C/EBPβ-dependent autocrine IL-6-loop. These findings partly reconcile the understanding of APR and may help to design a transcriptional suppressor of CRP for the treatment of cardiovascular disease.