D SHAPHyaluronan Complex and Inflammatory Bowel Disease

Crohn's disease and ulcerative colitis are the major chronic inflammatory diseases of the gastrointestinal tract. They are often referred to together as inflammatory bowel disease (IBD). The main pathological changes include an increase in intestinal mucosal mononuclear leukocytes and a dramatic hyperplasia of muscularis mucosae (75). The interaction between recruited leukocytes and mesenchymal smooth muscle cells is thought to be important in

Figure 4 The collagen-induced arthritis is ameliorated in mice deficient in the SHAP-hyaluronan complex. The mice were injected subcutaneously at the tail root with 0.2 mg of bovine type II collagen emulsified with complete Freund's adjuvant, then given a booster injection with 0.1 mg of bovine type II collagen at the same site 3 weeks later. The result shown is representative of two experiments.

0 10 20 30 40 50 60 Days after booster injection

Figure 4 The collagen-induced arthritis is ameliorated in mice deficient in the SHAP-hyaluronan complex. The mice were injected subcutaneously at the tail root with 0.2 mg of bovine type II collagen emulsified with complete Freund's adjuvant, then given a booster injection with 0.1 mg of bovine type II collagen at the same site 3 weeks later. The result shown is representative of two experiments.

the development and propagation of IBD. The etiology of IBD is multifactorial including viral infection. Using a cell-culturing system, De La Motte et al. (76,77) showed that viral infection or treatment with virus mimic polyinosinic acid/polycytidylic acid upregulated the production of hyaluronan in colon smooth muscle cells, and the hyaluronan was deposited in the extracellular space to form the pericellular 'coat' structure and the 'cable' structure spanning several cell lengths in contrast to the small patchy structure of hyaluronan before the stimulation. Again, the SHAP-hyaluronan complex was found to form in these upregulated hyaluronan molecules (77). Cell adhesion assay revealed that peripheral mononuclear cells or histiocytic lymphoma U937 cells bound specifically to the hyaluronan cables via their cell surface hyaluronan receptor CD44. Similar results were obtained with inflamed colon samples. The findings suggested that the SHAP-hyaluronan complex formed in inflammatory tissues plays a role in the activation/regulation of the infiltrating leukocytes. Interestingly, the hyaluronan coat structure exhibited no leukocyte adhesion activity although it was also positive for IaI. Two possibilities may be considered. First, the IaI associated with hyaluronan coat structures was not converted to the SHAP form because the antibody used for staining recognizes the heavy chain of IaI and SHAP and, second, a highly organized structure may be required for the leukocytes to adhere.

Another disease that may involve the formation of the SHAP-hyaluronan complex is multiple sclerosis (MS). MS is an inflammatory/demyelinating disease characterized by discrete acute and chronic lesions, plaques, but the mechanism of both the inflammatory/demyelinating and the neurodegenerative components of its pathogenesis are largely unknown. Because the disease progression is accompanied by a complex alteration of the extracellular matrix as a consequence of the breakdown of the blood-brain barrier, release and activation of extracellular proteases and synthesis of extracellular matrix, the relation between the dynamic alteration of the extracellular matrix and the pathogenesis is attracting more and more attention (78). Normal brain tissue as well as nearly acellular old MS plaques are negative for SHAP immunoreactivity, but relatively fresh plaques at the active phase of inflammation are positive for the SHAP-hyaluronan complex, implying a role for the complex in the pathogenesis of MS (our unpublished observations). As observed in the diseases mentioned above, CD44 is critical to the secondary leukocyte recruitment in experimental encephalomyelitis, an animal model for human MS (79).

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