Development of a peptide inhibitor of hyaluronan-mediated leukocyte trafficking.
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.
Mummert
M E
ME
Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9069, USA.
Mohamadzadeh
M
M
Mummert
D I
DI
Mizumoto
N
N
Takashima
A
A
D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D003877:Dermatitis, Contact / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005260:Female; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors / Q000502:physiology*; D007249:Inflammation; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007801:Langerhans Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019151:Peptide Library; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000276:immunology
D009842:Oligopeptides; D019151:Peptide Library; D006820:Hyaluronic Acid