Functional Switching of Macrophage Responses to Tumor Necrosis Factor-a (TNFa) by Interferons Implications for the Pleiotropic Activities of TNFa

Recent work conducted in our laboratory has been directed towards understanding the role of TNFa in stimulating the synthesis of two macrophage gene products, namely IGF-1, a growth factor implicated in wound repair and fibrosis, and complement component factor B (Bf), an alternative pathway complement component. The expression of these proteins is induced by hyaluronic acid and poly(I:C), respectively, although TNFa plays a requisite role in the expression of both proteins. The objective of this study was to determine the mechanism governing the dichotomy in the expression of IGF-1 and Bf by TNFa. First, we questioned if the diversity in IGF-1 and Bf synthesis was regulated at the level of TNF receptor usage. Second, based on earlier findings that IFNs contribute to the initiation of Bf expression, we determined if IFNs modulate the response of macrophages to TNFa. Our data show that differences in TNF receptor usage cannot fully explain the dichotomy in the expression of IGF-1 and Bf. However, prior exposure to IFN-ft or IFN-'y was found to be a dominant factor controlling the expression of these proteins, suppressing IGF-1, and enhancing Bf. These findings indicate that IFNs mediate a functional "switch" in the response of macrophages to TNFa and suggest that the pattern of cytokine expression by diverse macrophage stimuli is an important determinant of the eventual responses of macrophages to TNFa. (J. Clin. Invest. 1994. 93:1661-1669.) Data analysis. Results are presented as the mean ± standard error of the mean for three or more independent experiments. Comparisons between groups were made using the Student's paired t test.

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