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Isoforms and the Regulation of 
-Smooth Muscle Actin Gene Expression by IL-11
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
The role of IL-1
in inflammation is amply documented, but its ability to inhibit myofibroblast differentiation and, in particular, the suppression of 
-smooth muscle actin (-SMA) gene expression is less well understood. Because IL-1 can induce C/EBP expression, the role of C/EBP isoforms in IL-1 regulation of -SMA gene expression was investigated in rat lung myofibroblasts. The results showed that IL-1 inhibited -SMA expression in a dose-dependent manner, which was associated with stimulation of the expression of both C/EBP isoforms, liver-enriched activating protein (LAP) and liver-enriched inhibitory protein (LIP). However, a greater increase in LIP relative to LAP expression resulted in a reduced LAP/LIP ratio after IL-1 treatment. Transfection with an LAP-expressing plasmid stimulated, whereas an LIP-expressing plasmid inhibited, -SMA expression. Cells from C/EBP-deficient mice had reduced levels of -SMA expression and promoter activity, which failed to respond to IL-1 treatment. Sequence analysis identified the presence of a C/EBP consensus binding sequence in the -SMA promoter, which, when mutated, resulted in diminished promoter activity and abolished its responsiveness to IL-1 treatment. EMSA revealed binding of C/EBP to this C/EBP consensus binding sequence from the -SMA promoter. Finally, IL-1 enhanced the expression of eukaryotic initiation factor 4E, a stimulator of LIP expression, which may account for a mechanism by which IL-1 could alter the LAP/LIP ratio. These data taken together suggest that C/EBP isoforms regulate -SMA gene expression, and that its inhibition by IL-1 was due to preferential stimulation of LIP expression.
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