Proinsulin C-peptide stimulates a PKC/IκB/NF-κB signaling pathway to activate COX-2 gene transcription in Swiss 3T3 fibroblasts

Proinsulin C-peptide causes multiple molecular and physiological effects, and improves renal and neuronal dysfunction in patients with diabetes. However, whether C-peptide controls the inhibitor κB (IκB)/NF-κB- dependent transcription of genes, including inflammatory genes is unknown. Here we showed that 1 nM C-peptide increased the expression of cyclooxygenase-2 (COX-2) mRNA and its protein in Swiss 3T3 fibroblasts. Consistently, C-peptide enhanced COX-2 gene promoter-activity, which was inhibited by GF109203X and Go6976, specific PKC inhibitors, and BAY11-7082, a specific nuclear factor-κB (NF-κB) inhibitor, accompanied by increased phosphorylation and degradation of IκB. These results suggest that C-peptide stimulates the transcription of inflammatory genes via activation of a PKC/IκB/NF-κB signaling pathway.