CONSTITUTIVE AND INDUCIBLE EXPRESSION OF SKALP ELAFIN PROVIDES ANTI-ELASTASE DEFENSE IN HUMAN EPITHELIA/

Skin-derived antileukoproteinase (SKALP), also known as elafin, is a s erine proteinase inhibitor first discovered in keratinocytes from hype rproliferative human epidermis. In addition to the proteinase inhibiti ng domain which is directed against polymorphonuclear leukocyte (PMN) derived enzymes such as elastase and proteinase 3, SKALP contains mult iple transglutaminase (TGase) substrate domains which enable crosslink ing to extracellular and cell envelope proteins. Here we show that SKA LP is constitutively expressed in several epithelia that are continuou sly subjected to inflammatory stimuli, such as the oral cavity and the vagina where it co-localizes with type 1 TGase. All epithelia from st erile body cavities are negative for SKALP. In general, stratified squ amous epithelia are positive, whereas pseudostratified epithelia, simp le/glandular epithelia and normal epidermis are negative. SKALP was fo und in fetal tissues of the oral cavity from 17 wk gestation onwards w here it continued to be expressed up to adult life. Remarkably, in fet al epidermis SKALP was found from week 28 onwards, but was downregulat ed to undetectable levels in neonatal skin within three months, sugges ting a role during pregnancy in fete-maternal interactions or in the e arly maturation phase of the epidermis. Immunoelectron microscopy reve aled the presence of SKALP in secretory vesicles including the lamella r granules. In culture models for epidermal keratinocytes we found tha t expression of the endogenous SKALP gene provided protection against cell detachment caused by purified elastase or activated PMNs. Additio n of exogenous recombinant SKALP fully protected the keratinocytes aga inst PMN-dependent detachment whereas superoxide dismutase and catalas e were only marginally effective. These findings strongly suggest that the constitutive expression of SKALP in squamous epithelia, and the i nducible expression in epidermis participate in the control of epithel ial integrity, by inhibiting PMN derived proteinases.