Comparison of leptin- and interleukin-6-regulated expression of the rPAP gene family: evidence for differential co-regulatory signals.

The pancreatitis-associated protein (PAP)/regenerating protein (REG) family represents a complex group of small secretory proteins, which can function as acute phase reactants, lectins, antiapoptotic factors or growth factors for pancreatic beta-cells and neural cells. Transcriptional induction of rPAP/Reg genes was studied here in PC12 cells made responsive to leptin. Northern-blots showed quantitative differences in induction of four major family members by leptin and IL-6. Surprisingly, induction by leptin was strongly enhanced upon forskolin co-treatment whereas induction by IL-6 was counteracted. Functional studies involving progressive rPAP I promoter deletions showed, in the case of leptin, a clear correlation with predicted cis-regulatory elements. Leptin-induced stimulation was dependent on STAT3, since over-expression of dominant-negative STAT3, but not of dominant-negative STAT1, completely blocked transcriptional activation. In case of IL-6, an enhancer element outside the cloned promoter fragment is required for full stimulation. The effects of forskolin in a leptin and IL-6 context could not be explained at the promoter level, but rather events occurring upstream in the signalling cascade must be postulated to explain the differential co-regulatory effects.