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The Rel Family Member P50 Mediates Cytokine-Induced C-Reactive Protein Expression by a Novel Mechanism¹

Hyunjoo Cha-Molstad^*, Alok Agrawal, Dongxiao Zhang^2,*, David Samols^* and Irving Kushner^3,

^* Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106; and Department of Medicine, Case Western Reserve University, Metro Health Campus, Cleveland, OH 44109

Transcription of C-reactive protein (CRP) in Hep 3B cells is induced by IL-6, acting through C/EBP isoforms and STAT3. IL-1ß, which alone has no effect, greatly enhances IL-6-induced transcription by unknown mechanisms. Because IL-1ß activates the NF-B system, we explored the effects of overexpressed Rel family members on CRP expression. Unexpectedly, transactivation assays in transiently transfected Hep 3B cells showed p50 overexpression to markedly induce CRP transcription, acting in a region 3' to -86. In the presence of overexpressed p50, IL-1ß induced a 3-fold increase in CRP expression, and responses to IL-6 and to IL-6 plus IL-1ß were 4-fold greater than seen in cells without p50 overexpression. In contrast, overexpressed p65 abolished CRP induction by p50 and by cytokines. EMSA studies demonstrated that recombinant p50 bound to a nonconsensus B site overlapping the proximal C/EBP binding site on the CRP promoter. Mutation of a polypyrimidine tract in the p50-binding site inhibited the transactivating effect of cytokines. P50- but not p65-containing dimers were found in nuclei of Hep 3B cells 18 h after stimulation with IL-1ß, when C/EBPß is greatly activated, in the presence or absence of IL-6. These findings suggest that IL-1ß induces nuclear translocation of p50-containing dimers and that p50 interacts with C/EBPß activated by both IL-6 and IL-1ß to induce CRP expression.

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