KERATINOCYTES-ASSOCIATED CHEMOKINES AND ENZYMATICALLY QUIESCENT HEPARANASE INDUCE THE BINDING OF RESTING CD4(-CELLS() T)

Whether the chemokines macrophage inflammatory protein-1 beta (MIP-1 b eta) and regulated on activation normal T expressed and secreted (RANT ES), which interact specifically with glycosaminoglycans and thus medi ate the recruitment, attachment, and migration of leukocytes to vascul ar endothelia and extracellular matrix, are also involved in interacti ons between CD4(+) murine T lymphocytes and keratinocytes was examined . We have previously observed that depending on the local pH, a mammal ian extracellular matrix-degrading enzyme, endo-beta-D glucuronidase ( heparanase), which cleaves heparan sulfate proteoglycans, can function either as an enzyme or as an adhesion molecule for CD4(+) T lymphocyt es. Herein, the involvement of heparanase in T cell-keratinocyte inter actions was also probed, At 37 degrees C and pH 7.2, radioactively lab eled MIP-1 beta, RANTES, and heparanase bound to confluent layers of r esting keratinocyte in a saturable and an heparan sulfate- or heparin- dependent manner,and thereby induced the adhesion of resting CD4(+) T cells to keratinocytes. At a relatively acidic pH characteristic of in flammatory milieu, enzymatically active heparanase did not bind to the keratinocytes but, rather, inhibited the binding of MIP-1 beta, RANTE S, and the enzymatically quiescent heparanase to keratinocytes, These results suggest that certain chemokines and heparanase may function to restrict passing leukocytes, notably T lymphocytes, in the cutaneous micro-environment, a site which is continuously challenged with antige ns, These keratinocyte-bound lymphocytes can serve as a reservoir of i mmediate responders to immunological stimuli.