CYTOKINE AND CHEMOKINE REGULATION OF PROMMP-9 AND TIMP-1 PRODUCTION BY HUMAN PERIPHERAL-BLOOD LYMPHOCYTES

The production and activation-of matrix-degrading proteinases such as the matrix metalloproteinases (MMP) by lymphocytes is likely to be an important factor in facilitating lymphocyte trafficking through the en dothelial barrier and the extracellular matrix. Leukocyte infiltration into inflammatory sites occurs as a response to members of the chemok ine superfamily and other inflammatory mediators. In the present study , highly purified leukocyte subpopulations were cultured with or witho ut chemokines or cytokines, and their ability to express gelatinolytic MMPs and their inhibitors, the tissue inhibitors of metalloproteinase (TIMPs), was analyzed. In the absence of exogenous stimuli, purified CD4(+) T lymphocytes produced similar quantities of proMMP-9 and eleva ted levels of TIMP-1 compared with PBMC, while purified CD8(+) and CD3 (+) populations exhibited less MMP-9 and TIMP-1 activity. In compariso n, CD56(+) (NK) cells secreted barely detectable levels of proMMP-9 an d TIMP-1. The secretion of proMMP-9 by PBMC and purified CD3(+), CD4(), and CD8(+) lymphocytes was selectively modulated by beta chemokines and proinflammatory cytokines. ProMMP-9 secretion by CD3(+) and CD4(), but not by CD8(+) T cells was augmented in response to TNF-alpha an d IL-1, and down-regulated by IFN-gamma, while macrophage inflammatory protein (MIP)-1 alpha; MIP-1 beta, and RANTES (regulated upon activat ion and normally T cell expressed and secreted) (beta chemokines) up-r egulated the secretion of proMMP-9 by all of the lymphocyte subsets te sted. These results demonstrate that a number of proinflammatory cytok ines and chemokines differentially regulate proMMP-9 secretion from pu rified CD4(+) and CD8(+) lymphocytes, while for purified CD3(+) T cell s (consisting of CD4(+) and CD8(+) cells in approximately a 2:1 ratio) , a predominantly CD4(+) lymphocyte response profile was demonstrated.