TNF-ALPHA DIFFERENTIALLY REGULATES IA-ANTIGEN EXPRESSION AND MACROPHAGE TUMORICIDAL ACTIVITY IN 2 MURINE MACROPHAGE CELL-LINES

We have assessed tumor necrosis factor-α (TNF-α) production and its autocrine effects on activation in two murine macrophage cell lines which have distinct responses to the activation stimuli interferon-γ (IFN-γ) and bacterial lipopolysaccharide (LPS), and compared these responses to those observed in thioglycollate-elicited peritoneal macrophages. IFN-γ induced TNF-α production in RAW 264.7 cells and this induction was regulated at the transcriptional level. IFN-γ did not stimulate TNF-α production in either WEHI-3 cells or peritoneal macrophages, although MHC class II antigen expression was induced. LPS stimulated TNF-α production in the RAW 264.7 cell line and peritoneal macrophages; however, no TNF-α was detected in WEHI-3 cells activated with LPS. We also assessed the ability of endogenous TNF-α to serve as an autocrine regulator of two aspects of IFN-γ-mediated macrophage activation, namely, induction of antibody-independent tumoricidal activity and induction of MHC class II antigen expression. These studies revealed that TNF-α could act synergistically or antagonistically with IFN-γ in the regulation of these two functions, depending on both the macrophage population used and the function assessed. The results of our experiments suggest that the mechanism of induction of TNF-α production by IFN-γ or LPS, and the ultimate autocrine contribution of such TNF-α to a given activation response, is dependent on the activated macrophage target population under analysis. The WEHI-3 and RAW 264.7 cell lines provide a model system for comparative exploration of the mechanistic basis of this differential regulation. © 1992.