Abstract
Immunological cross-reactivity between tumor necrosis factor (TNF) binding proteins which are present in human urine (designated TBPI and TBPII) and two molecular species of the cell surface receptors for TNF is demonstrated. The two TNF receptors are shown to be immunologically distinct, to differ in molecular weight (58,000 and 73,000), and to be expressed differentially in different cells. It is further shown that polyclonal antibodies against one of the TNF binding proteins (TBPI) display, by virtue of their ability to bind the TNF receptor, activities which are very similar to those of TNF. These antibodies are cytotoxic to cells which are sensitive to TNF toxicity, induce resistance to TNF toxicity, enhance the incorporation of thymidine into normal fibroblasts, inhibit the growth of chlamydiae, and induce the synthesis of prostaglandin E2. Monovalent F(ab) fragments of the polyclonal antibodies lack TNF-like activities, but acquire them upon cross-linking with anti-F(ab)2 antibodies, suggesting that the ability of the anti-TBPI antibodies to mimic TNF correlates with their ability to cross-link the TNF receptors. This notion was further supported by data obtained in a comparative study of the TNF-like cytotoxicity of a panel of monoclonal antibodies against TBPI. The induction of TNF-like effects by antibodies to a TNF receptor suggests that TNF is not directly involved in intracellular signalling. Rather, it is the receptors to this cytokine which, when properly triggered in a process which appears to involve clustering of these receptors, transduce the signal for response to TNF into the cell's interior.
Highlights
Immunological Cross-reactivity between tumor necrosis factor (TNF)-binding Proteins Found in Human Urine (TBPI and TBPII) and Two Cell Surface TNF Receptors-Antibodies against two proteins purified from human urine that bind TNF had inhibitory effects on the binding of TNF to cells
We have suggested that the two urinary proteins (TNF-binding proteins TNF binding proteins (TBPI) and TBPII) constitute soluble forms of two molecular species of the cell surface receptors for TNF and that the two receptors which were recognized by those antibodies are expressed differentially in cells of different lines
Tagging the TNF receptors in cross-linking experiments with radiolabeled TNF revealed that the receptors in the HeLa and the U937 cells differ in size (58 kDa in HeLa and 73 kDa in the U937 cells, forming TNF-receptor conjugates of 75 and 90 kDa, respectively) (Fig. 1)
Summary
It is further shown that polyclonal antibodies against one of the TNF binding proteins (TBPI) display, by virtue of their ability to bind the TNF receptor, activities which are very similar to those of TNF. These antibodies are cytotoxic to cells which are sensitive to TNF toxicity, induce resistance to TNF toxicity, enhance the incorporation of thymidine into normal fibroblasts, inhibit the growth of chlamydiae, and induce the synthesis of prostaglandin Ea. Monovalent F(ab) fragments of the polyclonal antibodies lack TNF-like activities, but acquire them upon cross-linking with anti-F(ab) antibodies, suggesting that the ability of the anti-TBPI antibodies to mimic TNF correlates with their ability to cross-link the TNF receptors. **To whom correspondence and reprint requests should be addressed: Dept. of Molecular Genetics and Virology, The Weizmann
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