Specific-sized Hyaluronan Fragments Promote Expression of Human β-Defensin 2 in Intestinal Epithelium

• Published in: The Journal of biological chemistry Vol. 287; no. 36; pp. 30610 - 30624
• Main Authors: Hill, David R., Kessler, Sean P., Rho, Hyunjin K., Cowman, Mary K., de la Motte, Carol A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31.08.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; beta-Defensin; beta-Defensins - biosynthesis; beta-Defensins - genetics; beta-Defensins - immunology; Cell Line, Tumor; Colon - immunology; Colon - metabolism; Defensins; Dose-Response Relationship, Drug; Epithelium; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Gene Expression Regulation - immunology; Glycobiology and Extracellular Matrices; Humans; Hyaluronan; Hyaluronan Receptors - genetics; Hyaluronan Receptors - immunology; Hyaluronan Receptors - metabolism; Hyaluronate; Hyaluronic Acid - immunology; Hyaluronic Acid - metabolism; Hyaluronic Acid - pharmacology; Immunity, Innate - drug effects; Immunity, Innate - genetics; Immunity, Innate - immunology; Innate Barrier Defense; Intestinal Epithelium; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestine; Mice; Mice, Mutant Strains; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; Toll-Like Receptor 4 - metabolism; Hyaluronan; Innate Barrier Defense; Defensins; Intestine; beta-Defensin; Epithelium; Hyaluronate; Intestinal Epithelium
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.356238

Hyaluronan (HA) is a glycosaminoglycan polymer found in the extracellular matrix of virtually all mammalian tissues. Recent work has suggested a role for small, fragmented HA polymers in initiating innate defense responses in immune cells, endothelium, and epidermis through interaction with innate molecular pattern recognition receptors, such as TLR4. Despite these advances, little is known regarding the effect of fragmented HA at the intestinal epithelium, where numerous pattern recognition receptors act as sentinels of an innate defense response that maintains epithelial barrier integrity in the presence of abundant and diverse microbial challenges. Here we report that HA fragments promote expression of the innate antimicrobial peptide human β-defensin 2 (HβD2) in intestinal epithelial cells. Treatment of HT-29 colonic epithelial cells with HA fragment preparations resulted in time- and dose-dependent up-regulated expression of HβD2 protein in a fragment size-specific manner, with 35-kDa HA fragment preparations emerging as the most potent inducers of intracellular HβD2. Furthermore, oral administration of specific-sized HA fragments promotes the expression of an HβD2 ortholog in the colonic epithelium of both wild-type and CD44-deficient mice but not in TLR4-deficient mice. Together, our observations suggest that a highly size-specific, TLR4-dependent, innate defense response to fragmented HA contributes to intestinal epithelium barrier defense through the induction of intracellular HβD2 protein. Background: Hyaluronan fragments promote innate defense responses in a variety of cell types. Results: 35-kDa HA fragments induce expression of β-defensin in intestinal epithelium through a TLR4-dependent mechanism. Conclusion: Specific-sized HA fragments induce β-defensin expression in intestinal epithelium in vitro and in vivo. Significance: HA fragments may contribute to defense of the intestinal epithelium.