ACTIVATION OF THE LYMPHOTOXIN BETA-RECEPTOR BY CROSS-LINKING INDUCES CHEMOKINE PRODUCTION AND GROWTH ARREST IN A375 MELANOMA-CELLS

The lymphotoxin beta receptor (LT beta R) was originally described as a transcribed sequence encoded on human chromosome 12p, with homology to the TNF receptor family. Subsequently, a recombinant LT beta R was shown to bind LT alpha LT beta heteromeric complexes. In this study, w e have shown that LT beta R is expressed in a variety of tissues and c ell lines of monocytic lineage, as well as in fibroblast and human mel anoma cell lines. Unlike other members of the TNF receptor family, LT beta R is not expressed by peripheral blood T cells. A chimeric fusion protein consisting of the extracellular domain of LT beta R fused to the Fe region of human IgG1 was used to develop mAbs against LT beta R , Cross-linking LT beta R on A375 melanoma cells with these Abs genera ted an antiproliferative signal. In addition, the IL-8 and RANTES chem okines, early indicators of inflammation, were secreted by the A375 me lanoma line and the WI38VA13 fibroblast line in response to cross-link ing of LT beta R. These same activities could be induced by membrane-b ound and soluble LT beta and LT alpha LT beta oligomers.