Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 192, Issue 6, Pages 769-779Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.192.6.769
Keywords
glycosaminoglycan; leukocyte homing; contact hypersensitivity; Langerhans cell; phage display
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Funding
- NIAMS NIH HHS [R03-AR47402, R01-AR35068, R01-AR43777] Funding Source: Medline
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Hyaluronan (HA), a high molecular weight glycosaminoglycan, is expressed abundantly in the extracellular matrix and on cell surfaces. Although KA is known to bind many adhesion molecules, little information has been available with respect to its direct physiological role. In this study, we developed a novel 12-mer (GAHWQFNALTVR) peptide inhibitor of HA, termed Pep-1, by using phage display technology. Pep-1 showed specific binding to soluble, immobilized, and cell-associated forms of HA, and it inhibited leukocyte adhesion to HA substrates almost completely. Systemic, local, or topical administration of Pep-1 inhibited the expression of contact hypersensitivity responses in mice by blocking skin-directed homing of inflammatory leukocytes. Pep-1 also inhibited the sensitization phase by blocking hapten-triggered migration of Langerhans cells from the epidermis. These observations document that HA plays an essential role in two-way trafficking of leukocytes to and from an inflamed tissue, and thus provide technical and conceptual bases for testing the potential efficacy of HA inhibitors (e.g., Pep-1) for inflammatory disorders.
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