CYTOKINES CAUSE CULTURED RETINAL-PIGMENT EPITHELIAL-CELLS TO SECRETE METALLOPROTEINASES AND TO CONTRACT COLLAGEN GELS

Purpose. Because retinal pigment epithelial cells in epiretinal membra nes remodel and contract their surrounding extracellular matrix, inves tigations were performed to determine if these cells can produce matri x metalloproteinases and contract collagen gels in vitro in the presen ce of serum or cytokines. Methods. Cells were grown on collagen gels a nd their production of metalloproteinases was measured using zymograph y. Results. Cells grown in a three-dimensional collagen gel culture sy stem produce several latent metalloproteinases that are secreted into the gel and the surrounding medium. These include molecules of 49, 56, 66, and 100 kD. In addition, an enzyme that is probably the active fo rm of the 66 kD enzyme is present. When interleukin 1beta is added to the cultures, latent 49 kD and 100 kD gelatinase production is greatly stimulated and an active form of both enzymes is also observed in the medium. In contrast, transforming growth factor beta has no stimulato ry effect. The cells contract the collagen gel but this is small witho ut cytokines; however, contraction is greatly enhanced in the presence of serum or interleukin 1beta plus transforming growth factor beta. C ontraction is unlikely to be the result of metalloproteinase action on the underlying extracellular matrix because complete inhibition of th ese enzymes has little effect. Conclusions. These results show that cy tokines can cause cultured retinal pigment epithelial cells to produce metalloproteinases that can, when activated, degrade most collagens a nd other structural molecules in extracellular matrix. In addition, th ey can stimulate the contraction of extracellular matrix constituents but there is not a simple causal relationship between matrix remodelin g and contraction.