Metalloproteases and Serineproteases are Involved in the Cleavage of the Two Tumour Necrosis Factor (TNF) Receptors to Soluble Forms in the Myeloid Cell Lines U‐937 and THP‐1

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Abstract
The proteolytic processing of the two TNF receptors (TNF-R55 and TNF-R75) into soluble forms was investigated in the myeloid cell lines U-937 and THP-1. Phorbol myristate acetate (PMA) rapidly stimulated release of soluble forms of both TNF-receptors. Incubations were made with PMA and protease inhibitors directed against different target protease groups. The serineprotease inhibitors TPCK and dichloroisocoumarin and the metalloprotease inhibitor 1, 10-phenanthroline reduced PMA-induced release of both soluble receptor forms with about 60–70%. Furthermore, 1, 10-phenanthroline also reduced PMA-induced down-regulation of TNF-receptors in both cell lines as judged by TNF-binding to cells. Reduced down-regulation and TNF-receptor shedding by 1, 10-phenanthroline was reversed by Zn2+, indicating involvement of a Zn2+-dependent metalloprotease. Thus, both serine proteases and metalloproteases are involved in the processing of TNF-receptors.