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Lymphocyte Supernatant-induced Human Monocyte Tumoricidal Activity: Dependence on the Presence of -Interferon¹

Divisions of Hematology and Oncology [J. R. S., M. H., M. A. L., J. J. R.], Immunology [C. W.], Department of Medicine, and Department of Microbiology College of Biological Sciences [B. Z.], Ohio State University, Columbus, Ohio 43210, and Department of Microbiology, University of Kansas Medical Center, Kansas City, Kansas 66103 [R. H., M. P.]

Recently, -interferon (IFN-) has been shown to have the capacity to activate macrophages in several murine and human systems. The studies reported here were undertaken to determine the identity of the lymphokine responsible for activation of human monocytes to a tumoricidal state. Macrophage-activating factor (MAF) activity was assessed using a 24-h ⁵¹Cr release assay with human monocytes as effector cells and K-562 targets. Stimulated lymphocyte supernatants were produced by stimulation of peripheral blood mononuclear cells with concanavalin A in serum-free media. Interferon was detected in an antiviral assay. Four lines of evidence lead to the conclusion that MAF and IFN- are identical in this system: (a) fractionation of stimulated lymphocyte supernatants by adsorption chromatography, followed by anion or cation exchange chromatography (Mono-S, Mono-Q columns), resulted in nearly identical elution profiles of MAF and IFN activities. All of the individual fractions containing MAF activity were found to contain IFN in amounts corresponding to MAF activity. (b) Monoclonal antibody specific for IFN- neutralized the ability of stimulated lymphocyte supernatants to induce human monocyte tumoricidal activity. This antibody also neutralized the MAF activity of purified IFN- but not -interferon. (c) The biological MAF activity of activated lymphocyte supernatants and IFN- were similar. Dilution versus MAF activity for IFN- and stimulated lymphocyte supernatants exhibited identical slopes. Lymphocyte supernatants and IFN- demonstrated similar MAF activity on three effector cells: monocytes, in vitro-differentiated macrophages, and dexamethasone-differentiated macrophages. (d) Analysis of supernatants produced by five antigen-stimulated human T-cell clones demonstrated coordinate production of MAF and IFN. These results provide compelling evidence for support of the concept that IFN- is the major human lymphokine capable of inducing monocyte-macrophage tumoricidal activity.

¹ Supported by Grants CA33449-03 and CA09338.

² To whom requests for reprints should be addressed, at 410 West 10th Ave., Room N-1011, Columbus, OH 43210.

Received 8/ 6/84. Revised 12/14/84. Accepted 1/23/85.