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Cover  Active inflammatory bowel disease (Crohn's disease, ulcerative colitis) involves proliferation of mucosal smooth muscle cells and the production of an extracellular matrix rich in hyaluronan, which is fenestrated with mononuclear leukocytes. Components of this disease can be produced in culture when smooth muscle cells from normal human colon are treated with a viral mimetic (poly I:C) for 18 h, followed by the addition of exogenous leukocytes. The left image shows cables of hyaluronan (green) with adherent mononuclear leukocytes, stained with a monoclonal antibody to the cell surface hyaluronan receptor, CD44 (red). The right image shows a smooth muscle cell with hyaluronan (green) localized on the cell surface in patches and in long strands rising above the cell surface. The patches are intersected with filaments stained with polyclonal antisera to tumor necrosis factor-stimulated gene 6 (TSG-6; red), a hyaluronan-binding protein synthesized by the smooth muscle cells. Nuclei are stained with DAPI (blue). These observations, plus a strong link between viruses and the disease, implicate the engagement of CD44 on mononuclear leukocytes with the hyaluronan complex in the tissue matrix. Subsequent activation of the leukocytes bound to this hyaluronan matrix and the consequent release of cytokines, chemokines, and proteases may be a central mechanism in the pathology of these diseases. Confocal images are original and were generated by Carol de la Motte, Judith Drazba, Vincent Hascall, and Scott Strong in the Lerner Research Institute. The Cleveland Clinic Foundation, Cleveland, OH. Antisera to TSG-6 was produced by Anthony Day. Ref: Journal of Biological Chemistry [1999] 274, 30747-30755 Joe G. Hollyfield