TY - JOUR
T1 - Development of a peptide inhibitor of hyaluronan-mediated leukocyte trafficking
AU - Mummert, Mark E.
AU - Mohamadzadeh, Mansour
AU - Mummert, Diana I.
AU - Mizumoto, Norikatsu
AU - Takashima, Akira
PY - 2000
Y1 - 2000
N2 - Hyaluronan (HA), a high molecular weight glycosaminoglycan, is expressed abundantly in the extracellular matrix and on cell surfaces. Although HA 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.
AB - Hyaluronan (HA), a high molecular weight glycosaminoglycan, is expressed abundantly in the extracellular matrix and on cell surfaces. Although HA 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.
KW - Contact hypersensitivity
KW - Glycosaminoglycan
KW - Langerhans cell
KW - Leukocyte homing
KW - Phage display
UR - http://www.scopus.com/inward/record.url?scp=0033806427&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033806427&partnerID=8YFLogxK
U2 - 10.1084/jem.192.6.769
DO - 10.1084/jem.192.6.769
M3 - Article
C2 - 10993908
AN - SCOPUS:0033806427
SN - 0022-1007
VL - 192
SP - 769
EP - 779
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 6
ER -