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Regulation of hyaluronan synthase-2 expression in human intestinal mesenchymal cells: mechanisms of interleukin-1-mediated induction

Departments of ¹Surgery and ²Biochemistry, Virginia Commonwealth University, Richmond, Virginia

Submitted 1 November 2004 ; accepted in final form 21 January 2005

Elevated levels of hyaluronan are associated with numerous inflammatory diseases including inflammatory bowel disease. The purpose of this study was to determine whether a cause and effect relationship might exist among proinflammatory cytokines, IL-1, TNF-, IFN-, or transforming growth factor- (TGF-) and hyaluronan expression in human JDMC and, if so, to identify possible mechanisms involved in the induction of hyaluronan expression. TGF-, TNF-, and IFN- had little or no effect on hyaluronan production by these cells. Treatment with IL-1 induced an approximate 30-fold increase in the levels of hyaluronan in the medium of human jejunum-derived mesenchymal cells. Ribonuclease protection analysis revealed that steady-state transcript levels for hyaluronan synthase (HAS)2 were present at very low levels in untreated cells but increased as much as 18-fold in the presence of IL-1. HAS3 transcript levels were also increased slightly by exposure of these cells to IL-1. Expression of HAS1 transcripts was not detected under any condition in these cells. IL-1 induction of hyaluronan expression was inhibited in cells transfected with short interfering RNA corresponding to HAS2 transcripts. Inhibitors of the p38 and ERK1/2 mitogen-activated pathways but not JNK/SAPK blocked the IL-1-mediated induction of hyaluronan expression and the increase in HAS2 transcript expression. These results suggest that IL-1 induction of HAS2 expression involves multiple signaling pathways that act in concert, thus leading to an increase in expression of hyaluronan by jejunum-derived mesenchymal cells.

mitogen-activated pathways; inflammation; jejunum; nucleofection

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