Regulation of hyaluronan synthase-2 expression in human intestinal mesenchymal cells: mechanisms of interleukin-1beta-mediated induction.
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-1beta, TNF-alpha, IFN-gamma, or transforming growth factor-beta (TGF-beta) and hyaluronan expression in human JDMC and, if so, to identify possible mechanisms involved in the induction of hyaluronan expression. TGF-beta, TNF-alpha, and IFN-gamma had little or no effect on hyaluronan production by these cells. Treatment with IL-1beta 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-1beta. HAS3 transcript levels were also increased slightly by exposure of these cells to IL-1beta. Expression of HAS1 transcripts was not detected under any condition in these cells. IL-1beta 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-1beta-mediated induction of hyaluronan expression and the increase in HAS2 transcript expression. These results suggest that IL-1beta 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.
Ducale
Ashley E
AE
Dept. of Surgery, Virginia Commonwealth Univ., PO Box 980117, Richmond, VA 23298, USA.
Ward
Susan I
SI
Dechert
Tracey
T
Yager
Dorne R
DR
D018929:Cell Culture Techniques; D016207:Cytokines / Q000502:physiology; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D007249:Inflammation; D015212:Inflammatory Bowel Diseases / Q000503:physiopathology; D007375:Interleukin-1 / Q000502:physiology*; D007583:Jejunum / Q000473:pathology* / Q000502:physiology*; D008648:Mesoderm / Q000166:cytology; D015398:Signal Transduction; D014162:Transfection
D016207:Cytokines; D007375:Interleukin-1; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases