Hyaluronan-mediated leukocyte adhesion and dextran sulfate sodium-induced colitis are attenuated in the absence of signal transducer and activator of transcription 1.
Inflammatory bowel disease is a chronic inflammatory condition of the intestinal mucosa whose etiology is unclear but is likely to be multifactorial. We have shown previously that an increased amount of hyaluronan (HA) is present both in the inflamed mucosa of inflammatory bowel disease patients and in isolated human cells after polyI:C treatment. The signal transducer and activator of transcription (STAT)1 protein plays an important role in many signaling pathways that are associated with inflammation. We therefore investigated the role of STAT1 in adhesive interactions that occur between leukocytes and polyI:C-induced mucosal smooth muscle cells (M-SMCs). Activation of STAT1 was observed after the polyI:C treatment of M-SMCs. Specific phosphorylation of tyrosine and serine residues of STAT1 was observed in polyI:C-treated, but not untreated, M-SMC cultures. To evaluate further the role of STAT1, a corresponding STAT-1-null mouse was used. PolyI:C-induced, HA-mediated leukocyte adhesion to colon SMCs from STAT1-null mice was significantly decreased compared with that from wild-type control mice. In vivo, using the dextran sulfate sodium-induced model of colon inflammation, both tissue damage and HA deposition were attenuated in STAT1-null mice compared with that in wild-type control mice. Additionally, the inter-alpha-trypsin inhibitor (IalphaI), a proteoglycan essential for facilitating leukocyte binding to the HA matrix, was reduced in STAT1-null mice. Together, these results demonstrate that STAT1 plays an important role in HA-mediated inflammatory processes.
Bandyopadhyay
Sudip K
SK
Lerner Research Institute, Cleveland Clinic, Department of Pathobiology, Cleveland, OH 44195, USA. bandyos@ccf.org
de la Motte
Carol A
CA
Kessler
Sean P
SP
Hascall
Vincent C
VC
Hill
David R
DR
Strong
Scott A
SA
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D016264:Dextran Sulfate; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000172:deficiency* / Q000378:metabolism; D020298:U937 Cells
D050794:STAT1 Transcription Factor; D010768:Phosphoserine; D019000:Phosphotyrosine; D006820:Hyaluronic Acid; D016264:Dextran Sulfate; D011070:Poly I-C