Interleukin-6 (IL-6) production is up-regulated by several stimuli through the activation of transcription factors. We have previously demonstrated that CCAAT/enhancer binding protein homologous protein (CHOP) positively regulates IL-6 production at the transcriptional level in the human melanoma cell line A375. In this study, we provide evidence that CHOP up-regulates the IL-6 transcription without binding to the IL-6 promoter. CHOP dimerized more preferentially with an inhibitory isoform of nuclear factor for IL-6 expression (LIP (liver-enriched inhibitory protein)) than with a positively acting isoform (LAP, liver-enriched activator protein). These results indicate that CHOP plays an important role in IL-6 production without binding to its promoter, probably by trapping protein(s) such as LIP, which would otherwise inhibit IL-6 transcription.